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Su QY, Gao HY, Duan YR, Luo J, Wang WZ, Qiao XC, Zhang SX. The immunologic role of IL-23 in psoriatic arthritis: a potential therapeutic target. Expert Opin Biol Ther 2024; 24:1119-1132. [PMID: 39230202 DOI: 10.1080/14712598.2024.2401148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 07/25/2024] [Accepted: 09/02/2024] [Indexed: 09/05/2024]
Abstract
INTRODUCTION Psoriatic arthritis (PsA) is a debilitating chronic condition characterized by inflammation of the joints, bones, enthesis, and skin. The pivotal role of interleukin-23 (IL-23) in the pathogenesis of PsA has become increasingly evident. This proinflammatory cytokine is markedly elevated in patients with PsA, suggesting its potential as a therapeutic target. Consequently, IL-23 inhibitors have emerged as promising first-line biologic treatments for PsA. AREAS COVERED This review delves into the immunopathogenic mechanisms of IL-23 at the cellular and molecular levels in PsA. Furthermore, it provides the recent efficacy and safety profiles of IL-23 inhibitors. We conducted a literature search in PubMed for the following terms: 'IL-23 and psoriatic arthritis,' 'Ustekinumab,' 'Guselkumab,' 'Risankizumab,' and 'Tildrakizumab.' In addition, we retrieved clinical trials involving IL-23 inhibitors registered in ClinicalTrials.gov, EudraCT, and ICTRP. EXPERT OPINION Despite the promising outcomes observed with IL-23 inhibitors, several challenges persist. The long-term effects of these agents require further investigation through prospective studies, and their limited accessibility worldwide necessitates urgent attention. Additionally, ongoing research is warranted to explore other potential drug targets within the IL-23/IL-23 R axis. The development of reliable biomarkers could greatly enhance early detection, tailored management strategies, and personalized treatment approaches for patients with PsA.
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Affiliation(s)
- Qin-Yi Su
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi, China
- Ministry of Education, Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China
| | - Heng-Yan Gao
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi, China
- Ministry of Education, Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China
| | - Yue-Ru Duan
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi, China
- Ministry of Education, Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China
| | - Jing Luo
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi, China
- Ministry of Education, Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China
| | - Wei-Ze Wang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi, China
- Ministry of Education, Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China
| | - Xi-Chao Qiao
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi, China
- Ministry of Education, Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China
| | - Sheng-Xiao Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi, China
- Ministry of Education, Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China
- SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi medical university, Taiyuan, China
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Santiso A, Heinemann A, Kargl J. Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4. Pharmacol Rev 2024; 76:388-413. [PMID: 38697857 DOI: 10.1124/pharmrev.123.000901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 11/15/2023] [Accepted: 11/20/2023] [Indexed: 05/05/2024] Open
Abstract
The involvement of the prostaglandin E2 (PGE2) system in cancer progression has long been recognized. PGE2 functions as an autocrine and paracrine signaling molecule with pleiotropic effects in the human body. High levels of intratumoral PGE2 and overexpression of the key metabolic enzymes of PGE2 have been observed and suggested to contribute to tumor progression. This has been claimed for different types of solid tumors, including, but not limited to, lung, breast, and colon cancer. PGE2 has direct effects on tumor cells and angiogenesis that are known to promote tumor development. However, one of the main mechanisms behind PGE2 driving cancerogenesis is currently thought to be anchored in suppressed antitumor immunity, thus providing possible therapeutic targets to be used in cancer immunotherapies. EP2 and EP4, two receptors for PGE2, are emerging as being the most relevant for this purpose. This review aims to summarize the known roles of PGE2 in the immune system and its functions within the tumor microenvironment. SIGNIFICANCE STATEMENT: Prostaglandin E2 (PGE2) has long been known to be a signaling molecule in cancer. Its presence in tumors has been repeatedly associated with disease progression. Elucidation of its effects on immunological components of the tumor microenvironment has highlighted the potential of PGE2 receptor antagonists in cancer treatment, particularly in combination with immune checkpoint inhibitor therapeutics. Adjuvant treatment could increase the response rates and the efficacy of immune-based therapies.
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Affiliation(s)
- Ana Santiso
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Julia Kargl
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
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Feng B, Pan B, Huang J, Du Y, Wang X, Wu J, Ma R, Shen B, Huang G, Feng J. PDE4D/cAMP/IL-23 axis determines the immunotherapy efficacy of lung adenocarcinoma via activating the IL-9 autocrine loop of cytotoxic T lymphocytes. Cancer Lett 2023; 565:216224. [PMID: 37196909 DOI: 10.1016/j.canlet.2023.216224] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 05/08/2023] [Accepted: 05/09/2023] [Indexed: 05/19/2023]
Abstract
Although immunotherapy has changed the prognosis of many advanced malignancies including lung adenocarcinoma (LUAD), many patients are insensitive to the drugs, with the mechanisms yet to be elucidated. Herein, we identified PDE4D as an immunotherapy efficacy-related gene through bioinformatics screening. By using a co-culture system of LUAD cells and tumor-cell-specific CD8+ T cells, a functional PDE4D/cAMP/IL-23 axis was further revealed in LUAD cells. Fluorescent multiplex immunohistochemistry analysis of patient-derived samples and the in vivo mouse LUAD xenograft tumors revealed not only the colocalization of IL-23 and CD8+ T cells but also the immune potentiating effect of IL-23 on cytotoxic T lymphocytes (CTLs) in LUAD tissues. Through transcriptome sequencing and functional validations, IL-23 was proven to up-regulate IL-9 expression in CTLs via activating the NF-κB signaling, leading to elevated productions of immune effector molecules and enhanced efficacy of antitumor immunotherapy. Interestingly, an autocrine loop of IL-9 was also uncovered during this process. In conclusion, PDE4D/cAMP/IL-23 axis determines the immunotherapy efficacy of human LUAD. This effect is mediated by the activation of an NF-κB-dependent IL-9 autocrine loop in CTLs.
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Affiliation(s)
- Bing Feng
- Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, China
| | - Banzhou Pan
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, China
| | - Jiayuan Huang
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, China
| | - Yuxin Du
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, China
| | - Xin Wang
- Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, China
| | - Jianzhong Wu
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, China
| | - Rong Ma
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, China
| | - Bo Shen
- Department of Medical Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, China.
| | - Guichun Huang
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210093, China.
| | - Jifeng Feng
- Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, 42 Baiziting, Nanjing, 210009, China.
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Paroli M, Caccavale R, Fiorillo MT, Spadea L, Gumina S, Candela V, Paroli MP. The Double Game Played by Th17 Cells in Infection: Host Defense and Immunopathology. Pathogens 2022; 11:pathogens11121547. [PMID: 36558881 PMCID: PMC9781511 DOI: 10.3390/pathogens11121547] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
T-helper 17 (Th17) cells represent a subpopulation of CD4+ T lymphocytes that play an essential role in defense against pathogens. Th17 cells are distinguished from Th1 and Th2 cells by their ability to produce members of the interleukin-17 (IL-17) family, namely IL-17A and IL-17F. IL-17 in turn induces several target cells to synthesize and release cytokines, chemokines, and metalloproteinases, thereby amplifying the inflammatory cascade. Th17 cells reside predominantly in the lamina propria of the mucosa. Their main physiological function is to maintain the integrity of the mucosal barrier against the aggression of infectious agents. However, in an appropriate inflammatory microenvironment, Th17 cells can transform into immunopathogenic cells, giving rise to inflammatory and autoimmune diseases. This review aims to analyze the complex mechanisms through which the interaction between Th17 and pathogens can be on the one hand favorable to the host by protecting it from infectious agents, and on the other hand harmful, potentially generating autoimmune reactions and tissue damage.
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Affiliation(s)
- Marino Paroli
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
- Correspondence:
| | - Rosalba Caccavale
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Maria Teresa Fiorillo
- Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy
| | - Luca Spadea
- Post Graduate School of Public Health, University of Siena, 53100 Siena, Italy
| | - Stefano Gumina
- Department of Anatomy, Histology, Legal Medicine and Orthopedics, Sapienza University of Rome, 00185 Rome, Italy
| | - Vittorio Candela
- Department of Anatomy, Histology, Legal Medicine and Orthopedics, Sapienza University of Rome, 00185 Rome, Italy
| | - Maria Pia Paroli
- Eye Clinic, Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy
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5
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Simard M, Morin S, Ridha Z, Pouliot R. Current knowledge of the implication of lipid mediators in psoriasis. Front Immunol 2022; 13:961107. [PMID: 36091036 PMCID: PMC9459139 DOI: 10.3389/fimmu.2022.961107] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
The skin is an organ involved in several biological processes essential to the proper functioning of the organism. One of these essential biological functions of the skin is its barrier function, mediated notably by the lipids of the stratum corneum, and which prevents both penetration from external aggression, and transepidermal water loss. Bioactive lipid mediators derived from polyunsaturated fatty acids (PUFAs) constitute a complex bioactive lipid network greatly involved in skin homeostasis. Bioactive lipid mediators derived from n-3 and n-6 PUFAs have well-documented anti- and pro-inflammatory properties and are recognized as playing numerous and complex roles in the behavior of diverse skin diseases, including psoriasis. Psoriasis is an inflammatory autoimmune disease with many comorbidities and is associated with enhanced levels of pro-inflammatory lipid mediators. Studies have shown that a high intake of n-3 PUFAs can influence the development and progression of psoriasis, mainly by reducing the severity and frequency of psoriatic plaques. Herein, we provide an overview of the differential effects of n-3 and n-6 PUFA lipid mediators, including prostanoids, hydroxy-fatty acids, leukotrienes, specialized pro-resolving mediators, N-acylethanolamines, monoacylglycerols and endocannabinoids. This review summarizes current findings on lipid mediators playing a role in the skin and their potential as therapeutic targets for psoriatic patients.
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Affiliation(s)
- Mélissa Simard
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/Laboratoire d’Organogénèse EXpérimentale (LOEX), Axe Médecine Régénératrice, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec, Québec, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec, QC, Canada
| | - Sophie Morin
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/Laboratoire d’Organogénèse EXpérimentale (LOEX), Axe Médecine Régénératrice, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec, Québec, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec, QC, Canada
| | - Zainab Ridha
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/Laboratoire d’Organogénèse EXpérimentale (LOEX), Axe Médecine Régénératrice, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec, Québec, QC, Canada
| | - Roxane Pouliot
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/Laboratoire d’Organogénèse EXpérimentale (LOEX), Axe Médecine Régénératrice, Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec, Québec, QC, Canada
- Faculté de Pharmacie, Université Laval, Québec, QC, Canada
- *Correspondence: Roxane Pouliot,
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6
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Lee KMC, Sherlock JP, Hamilton JA. The role of interleukin (IL)-23 in regulating pain in arthritis. Arthritis Res Ther 2022; 24:89. [PMID: 35468842 PMCID: PMC9036686 DOI: 10.1186/s13075-022-02777-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/12/2022] [Indexed: 11/10/2022] Open
Abstract
Current understanding of IL-23 biology, with its link to other pro-inflammatory cytokines, for example, IL-17 and granulocyte macrophage-colony stimulating factor (GM-CSF), is primarily focused on T lymphocyte-mediated inflammation/autoimmunity. Pain is a significant symptom associated with many musculoskeletal conditions leading to functional impairment and poor quality of life. While the role of IL-23 in arthritis has been studied in mouse models of adaptive immune-mediated arthritis using targeted approaches (e.g., monoclonal antibody (mAb) neutralization), the literature on IL-23 and arthritis pain is limited. Encouragingly, the anti-IL-23p19 mAb, guselkumab, reduces pain in psoriatic arthritis patients. Recent evidence has suggested a new biology for IL-23, whereby IL-23 is required in models of innate immune-mediated arthritis and its associated pain with its action being linked to a GM-CSF-dependent pathway (the so-called GM-CSF➔CCL17 pathway). This Commentary discusses the current understanding of potential cytokine networks involving IL-23 in arthritis pain and provides a rationale for future clinical studies targeting IL-23p19 in arthritis pain.
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Affiliation(s)
- Kevin M-C Lee
- The University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
| | - Jonathan P Sherlock
- Janssen Research and Development LLC, Spring House, PA, USA.,Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - John A Hamilton
- The University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, Victoria, Australia
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7
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Abstract
Over the past decades, tremendous success in the treatment of psoriasis has been achieved using biologics, such as neutralizing antibodies against TNF/TNFR, IL-23, and IL-17A/IL-17RA. Although psoriatic skin lesions appear to resolve after treatment with these biologics, lesions often recur after therapy is discontinued or during therapy. Memory T cells residing in the skin have been considered as the major driver of psoriasis relapse. However, whether structural cells in the skin such as keratinocytes and fibroblasts are involved in the relapse of psoriasis is unknown. In this review, we outline the therapeutic rationale of biologics used in the treatment of psoriasis, summarize different clinical features of psoriasis relapse on the basis of preclinical and clinical data, and specifically discuss how memory T cells and structural cells in the skin are involved in psoriasis relapse. Finally, we discuss the future challenges in the basic or clinical research on psoriasis.
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8
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Tsirvouli E, Ashcroft F, Johansen B, Kuiper M. Logical and experimental modeling of cytokine and eicosanoid signaling in psoriatic keratinocytes. iScience 2021; 24:103451. [PMID: 34877506 PMCID: PMC8633970 DOI: 10.1016/j.isci.2021.103451] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/28/2021] [Accepted: 11/11/2021] [Indexed: 12/11/2022] Open
Abstract
Psoriasis is a chronic skin disease, in which immune cells and keratinocytes keep each other in a state of inflammation. It is believed that phospholipase A2 (PLA2)-dependent eicosanoid release plays a key role in this. T-helper (Th) 1-derived cytokines are established activators of phospholipases in keratinocytes, whereas Th17-derived cytokines have largely unknown effects. Logical model simulations describing the function of cytokine and eicosanoid signaling networks combined with experimental data suggest that Th17 cytokines stimulate proinflammatory cytokine expression in psoriatic keratinocytes via activation of cPLA2α-Prostaglandin E2-EP4 signaling, which could be suppressed using the anti-psoriatic calcipotriol. cPLA2α inhibition and calcipotriol distinctly regulate expression of key psoriatic genes, possibly offering therapeutic advantage when applied together. Model simulations additionally suggest EP4 and protein kinase cAMP-activated catalytic subunit alpha as drug targets that may restore a normal phenotype. Our work illustrates how the study of complex diseases can benefit from an integrated systems approach.
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Affiliation(s)
- Eirini Tsirvouli
- Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Felicity Ashcroft
- Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Berit Johansen
- Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Martin Kuiper
- Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim, Norway
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9
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Das UN. Molecular biochemical aspects of salt (sodium chloride) in inflammation and immune response with reference to hypertension and type 2 diabetes mellitus. Lipids Health Dis 2021; 20:83. [PMID: 34334139 PMCID: PMC8327432 DOI: 10.1186/s12944-021-01507-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 07/14/2021] [Indexed: 12/18/2022] Open
Abstract
Obesity, insulin resistance, type 2 diabetes mellitus (T2DM) and hypertension (HTN) are common that are associated with low-grade systemic inflammation. Diet, genetic factors, inflammation, and immunocytes and their cytokines play a role in their pathobiology. But the exact role of sodium, potassium, magnesium and other minerals, trace elements and vitamins in the pathogenesis of HTN and T2DM is not known. Recent studies showed that sodium and potassium can modulate oxidative stress, inflammation, alter the autonomic nervous system and induce dysfunction of the innate and adaptive immune responses in addition to their action on renin-angiotensin-aldosterone system. These actions of sodium, potassium and magnesium and other minerals, trace elements and vitamins are likely to be secondary to their action on pro-inflammatory cytokines IL-6, TNF-α and IL-17 and metabolism of essential fatty acids that may account for their involvement in the pathobiology of insulin resistance, T2DM, HTN and autoimmune diseases.
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Affiliation(s)
- Undurti N Das
- UND Life Sciences, 2221 NW 5th St, Battle Ground, WA, 98604, USA.
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10
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Polese B, Thurairajah B, Zhang H, Soo CL, McMahon CA, Fontes G, Hussain SNA, Abadie V, King IL. Prostaglandin E 2 amplifies IL-17 production by γδ T cells during barrier inflammation. Cell Rep 2021; 36:109456. [PMID: 34320346 DOI: 10.1016/j.celrep.2021.109456] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 05/21/2021] [Accepted: 07/07/2021] [Indexed: 12/21/2022] Open
Abstract
Interleukin-17 (IL-17)-producing γδ (γδ17) T cells are innate-like lymphocytes that contribute to protective anti-microbial responses but are also implicated in pathogenic inflammation at barrier sites. Understanding tissue-specific signals that regulate this subset is important to boost host defense mechanisms, but also to mitigate immunopathology. Here, we demonstrate that prostaglandin E2 (PGE2), a cyclooxygenase-dependent member of the eicosanoid family, directly enhances cytokine production by circulating and tissue-specific γδ17 T cells in vitro. Gain- and loss-of-function in vivo approaches further reveal that although provision of PGE2 amplifies psoriasiform inflammation, ablation of host mPGES1-dependent PGE2 synthesis is dispensable for cutaneous γδ17 T cell activation. By contrast, loss of endogenous PGE2 production or depletion of the gut microbiota compromises intestinal γδ17 T cell responses and increases disease severity during experimental colitis. Together, our results demonstrate how a lipid mediator can synergize with tissue-specific signals to enhance innate lymphocyte production of IL-17 during barrier inflammation.
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Affiliation(s)
- Barbara Polese
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Bavanitha Thurairajah
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Hualin Zhang
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Cindy Leung Soo
- McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Clara A McMahon
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Ghislaine Fontes
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Sabah N A Hussain
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Valerie Abadie
- Section of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Irah L King
- Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; McGill Interdisciplinary Initiative in Infection and Immunity, Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
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Park HS, Choi S, Back YW, Lee KI, Choi HG, Kim HJ. Mycobacterium tuberculosis RpfE-Induced Prostaglandin E2 in Dendritic Cells Induces Th1/Th17 Cell Differentiation. Int J Mol Sci 2021; 22:ijms22147535. [PMID: 34299161 PMCID: PMC8304802 DOI: 10.3390/ijms22147535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/05/2021] [Accepted: 07/11/2021] [Indexed: 01/13/2023] Open
Abstract
Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.
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12
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Paiva IA, Badolato-Corrêa J, Familiar-Macedo D, de-Oliveira-Pinto LM. Th17 Cells in Viral Infections-Friend or Foe? Cells 2021; 10:cells10051159. [PMID: 34064728 PMCID: PMC8151546 DOI: 10.3390/cells10051159] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/20/2021] [Accepted: 04/28/2021] [Indexed: 12/12/2022] Open
Abstract
Th17 cells are recognized as indispensable in inducing protective immunity against bacteria and fungi, as they promote the integrity of mucosal epithelial barriers. It is believed that Th17 cells also play a central role in the induction of autoimmune diseases. Recent advances have evaluated Th17 effector functions during viral infections, including their critical role in the production and induction of pro-inflammatory cytokines and in the recruitment and activation of other immune cells. Thus, Th17 is involved in the induction both of pathogenicity and immunoprotective mechanisms seen in the host's immune response against viruses. However, certain Th17 cells can also modulate immune responses, since they can secrete immunosuppressive factors, such as IL-10; these cells are called non-pathogenic Th17 cells. Here, we present a brief review of Th17 cells and highlight their involvement in some virus infections. We cover these notions by highlighting the role of Th17 cells in regulating the protective and pathogenic immune response in the context of viral infections. In addition, we will be describing myocarditis and multiple sclerosis as examples of immune diseases triggered by viral infections, in which we will discuss further the roles of Th17 cells in the induction of tissue damage.
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13
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Łukasik Z, Gracey E, Venken K, Ritchlin C, Elewaut D. Crossing the boundaries: IL-23 and its role in linking inflammation of the skin, gut and joints. Rheumatology (Oxford) 2021; 60:iv16-iv27. [PMID: 33961030 PMCID: PMC8527243 DOI: 10.1093/rheumatology/keab385] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/17/2021] [Indexed: 11/17/2022] Open
Abstract
Several lines of evidence point towards the central role of IL-23 as a crucial inflammatory mediator in the pathogenesis of SpA—a group of inflammatory arthritic diseases whose symptoms span the skin, gastrointestinal tract and joints. While therapeutic blockade of IL-23 proved successful in the treatment of IBD, psoriatic skin disease and peripheral SpA, it failed in patients suffering from SpA with predominantly axial involvement. Here we review state-of-the-art discoveries on IL-23 signalling pathways across target tissues involved in SpA. We discuss the discrepancies in resident IL-23–responding cells and their downstream activities across skin, gut and joint that shape the unique immunological landscape of SpA.
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Affiliation(s)
- Zuzanna Łukasik
- Department of Internal Medicine and Pediatrics, UZ Ghent, Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent University, Belgium
| | - Eric Gracey
- Department of Internal Medicine and Pediatrics, UZ Ghent, Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent University, Belgium
| | - Koen Venken
- Department of Internal Medicine and Pediatrics, UZ Ghent, Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent University, Belgium
| | - Christopher Ritchlin
- Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Dirk Elewaut
- Department of Internal Medicine and Pediatrics, UZ Ghent, Ghent University, Ghent, Belgium.,VIB Center for Inflammation Research, Ghent University, Belgium.,Ghent Gut Inflammation Group, Ghent University, Ghent, Belgium
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14
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Abstract
In inflammatory rheumatic disorders, the immune system attacks and damages the connective tissues and invariably internal organs. During the past decade, remarkable advances having been made towards our understanding on the cellular and molecular mechanisms involved in rheumatic diseases. The discovery of IL-23/IL-17 axis and the delineation of its important role in the inflammation led to the introduction of many needed new therapeutic tools. We will present an overview of the rationale for targeting therapeutically the IL-23/IL-17 axis in rheumatic diseases and the clinical benefit which has been realized so far. Finally, we will discuss the complex interrelationship between IL-23 and IL-17 and the possible uncoupling in certain disease settings.
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15
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Woodward DF, Wang JW, Spada CS, Carling RW, Martos JL, Pettit S, Kangasmetsa J, Waterbury LD, Lawrence M, Hu W, Poloso NJ. A Second Generation Prostanoid Receptor Antagonist Acting at Multiple Receptor Subtypes. ACS Pharmacol Transl Sci 2020; 3:1199-1210. [PMID: 33344897 DOI: 10.1021/acsptsci.0c00118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Indexed: 12/15/2022]
Abstract
It has previously been reported that a prototypical compound (AGN 211377), which blocks pro-inflammatory prostanoid receptors (DP1, DP2, EP1, EP4, FP, TP) and leaves open IP and EP2 receptors so that their anti-inflammatory properties could be exerted, produced superior inhibitory effects on cytokine release from human macrophages compared to cyclooxygenase (COX) inhibitors. This favorable activity profile translated into animal studies, with AGN 211377 exceeding the level of inhibition afforded by COX inhibition. AGN 211377 was not, however, a practical drug candidate, having poor bioavailability and cost of goods concerns. Compound 1 (designated AGN 225660) represents a second-generation compound with an entirely different "druggable" core structure. Such a dramatic change in chemical scaffold created uncertainty with respect to matching the effects of AGN 211377. AGN 225660 inhibited RANTES, IL-8, and MCP-1 secretion by at least 50%, from TNFα activated human macrophages. Although AGN 225660 reduced TNFα-evoked MCP-1 release from human monocyte-derived macrophages, it increased LPS-induced MCP-1 secretion (up to 2-fold) from human monocyte-derived dendritic cells. However, AGN 225660 inhibited the release of IL12p 70 and IL-23 from human monocyte-derived dendritic cells stimulated by LPS by more than 70%. This effect of AGN 225660 was reproduced in part by the prototype compound AGN 211377 and a combination of selective DP1, EP1, EP4, FP, and TP antagonists. These findings suggest important effects on T cell skewing and disease modification by this class of therapeutic agents. AGN 225660 exhibited good ocular bioavailability and was active in reducing ocular inflammation associated with phacoemulsification surgery, LPS, and arachidonic acid induced uveitis.
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Affiliation(s)
- David F Woodward
- Research and External Scientific Innovation, Allergan Inc., Irvine, California 92612, United States
| | - Jenny W Wang
- Research and External Scientific Innovation, Allergan Inc., Irvine, California 92612, United States
| | - Clayton S Spada
- Research and External Scientific Innovation, Allergan Inc., Irvine, California 92612, United States
| | | | - Jose L Martos
- Discovery Department, Selcia Ltd., Ongar, Essex, CM5 0GS, U.K
| | - Simon Pettit
- Discovery Department, Selcia Ltd., Ongar, Essex, CM5 0GS, U.K
| | | | | | | | - Wenzheng Hu
- RxGen Inc., Hamden, Connecticut 06511, United States
| | - Neil J Poloso
- Research and External Scientific Innovation, Allergan Inc., Irvine, California 92612, United States
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16
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Lee KMC, Zhang Z, Achuthan A, Fleetwood AJ, Smith JE, Hamilton JA, Cook AD. IL-23 in arthritic and inflammatory pain development in mice. Arthritis Res Ther 2020; 22:123. [PMID: 32471485 PMCID: PMC7345543 DOI: 10.1186/s13075-020-02212-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
Background The cytokine, interleukin-23 (IL-23), can be critical for the progression of inflammatory diseases, including arthritis, and is often associated with T lymphocyte biology. We previously showed that certain lymphocyte-independent, inflammatory arthritis and pain models have a similar requirement for tumour necrosis factor (TNF), granulocyte macrophage-colony stimulating factor (GM-CSF), and C-C motif ligand 17 (CCL17). Given this correlation in cytokine requirements, we explored whether IL-23 might interact with this cytokine cluster in the control of arthritic and inflammatory pain. Methods The role of IL-23 in the development of pain-like behaviour was investigated using mouse arthritis models (zymosan-induced arthritis and GM-CSF-, TNF-, and CCL17-driven monoarticular arthritis) and inflammatory pain models (intraplantar zymosan, GM-CSF, TNF, and CCL17). Additionally, IL-23-induced inflammatory pain was measured in GM-CSF−/−, Tnf−/−, and Ccl17E/E mice and in the presence of indomethacin. Pain-like behaviour and arthritis were assessed by relative weight distribution in hindlimbs and histology, respectively. Cytokine mRNA expression in knees and paw skin was analysed by quantitative PCR. Blood and synovial cell populations were analysed by flow cytometry. Results We report, using Il23p19−/− mice, that innate immune (zymosan)-driven arthritic pain-like behaviour (herein referred to as pain) was completely dependent upon IL-23; optimal arthritic disease development required IL-23 (P < 0.05). Zymosan-induced inflammatory pain was also completely dependent on IL-23. In addition, we found that exogenous TNF-, GM-CSF-, and CCL17-driven arthritic pain, as well as inflammatory pain driven by each of these cytokines, were absent in Il23p19−/− mice; optimal disease in these mBSA-primed models was dependent on IL-23 (P < 0.05). Supporting this cytokine connection, it was found conversely that IL-23 (200 ng) can induce inflammatory pain at 4 h (P < 0.0001) with a requirement for each of the other cytokines as well as cyclooxygenase activity. Conclusions These findings indicate a role for IL-23 in innate immune-mediated arthritic and inflammatory pain with potential links to TNF, GM-CSF, CCL17, and eicosanoid function.
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Affiliation(s)
- Kevin M-C Lee
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia.
| | - Zihao Zhang
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia
| | - Adrian Achuthan
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia
| | - Andrew J Fleetwood
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia
| | - Julia E Smith
- Adaptive Immunity, GSK Medicines Research Centre, Stevenage, Hertfordshire, UK
| | - John A Hamilton
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia.,Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, Victoria, Australia
| | - Andrew D Cook
- Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, 3050, Australia
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17
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Honda T, Kabashima K. Prostanoids and leukotrienes in the pathophysiology of atopic dermatitis and psoriasis. Int Immunol 2020; 31:589-595. [PMID: 30715370 DOI: 10.1093/intimm/dxy087] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 01/15/2019] [Indexed: 12/25/2022] Open
Abstract
Lipid mediators, such as prostanoids and leukotrienes (LTs), exert a range of actions through their own receptors on cell surfaces in various pathophysiological conditions. It has been reported that the production of prostanoids and LTs is significantly elevated in the skin lesions of some chronic inflammatory skin diseases, such as atopic dermatitis (AD) and psoriasis, showing the possible involvement of these lipid mediators in the development of those diseases. Although the actual significance of these lipid mediators in humans is still unclear, the findings from studies in mice suggest diverse roles of the lipid mediators in the progression or regulation of these diseases. For example, in a mouse AD model, prostaglandin D2 inhibits the induction of Th2 cells through DP receptor on Langerhans cells, while it promotes infiltration of Th2 cells through chemoattractant receptor-homologous molecule expressed on Th2 cells. In a psoriasis model, thromboxane A2-TP signaling promotes psoriatic dermatitis by facilitating IL-17 production from γδ T cells. In this short review, we summarize the current findings on the roles of prostanoids and LTs in AD and psoriasis as revealed by studies in mice, and discuss the potential of these lipid mediators as therapeutic targets in humans.
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Affiliation(s)
- Tetsuya Honda
- Department of Dermatology, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto, Japan
| | - Kenji Kabashima
- Department of Dermatology, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto, Japan.,Singapore Immunology Network (SIgN) and Skin Research Institute of Singapore (SRIS), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
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18
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Chyuan IT, Lai JH. New insights into the IL-12 and IL-23: From a molecular basis to clinical application in immune-mediated inflammation and cancers. Biochem Pharmacol 2020; 175:113928. [PMID: 32217101 DOI: 10.1016/j.bcp.2020.113928] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Accepted: 03/19/2020] [Indexed: 12/31/2022]
Abstract
The cytokines interleukin-12 (IL-12) and IL-23 share a common IL-12/IL-23p40 subunit in structure and play a central role in T cell-mediated responses in inflammation. Over-activated IL-12 and IL-23 signaling drives aberrant T helper (Th) 1 and Th17 immune responses and contributes to immune-mediated diseases. Evidence from genome-wide association studies has shown that genetic alterations in the IL-12/IL-23 signaling pathways have significant links with chronic inflammation. In addition, accumulating evidence from animal models and clinical trials has provided insights into the effectiveness of blocking the IL-12/IL-23 pathways in immune regulation, broadening the clinical indications of IL-12/IL-23 pathway effectors in immune-mediated diseases. More recently, it has been addressed that the balance between IL and 12 and IL-23 is also critical in carcinogenesis. IL-12- and IL-23-driven T cell cytokines are especially important in controlling tumor initiation, growth, and metastasis, and thus, the IL-12/IL-23 pathway may be a promising target for immunotherapy. This review focuses on IL-12/IL-23 signal transduction and biological functionality in autoimmunity and oncoimmunology. We discuss the therapeutic rationale for targeting these cytokines to treat immune-mediated diseases and issues regarding their inadvertent consequences in the balance of host defense and tumor surveillance and summarize their recent clinical applications in immune-mediated diseases.
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Affiliation(s)
- I-Tsu Chyuan
- Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan; Department of Medical Research, Cathay General Hospital, Taipei, Taiwan; School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Jenn-Haung Lai
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan, Taiwan; Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan.
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19
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Wu JMF, Cheng YY, Tang TWH, Shih C, Chen JH, Hsieh PCH. Prostaglandin E 2 Receptor 2 Modulates Macrophage Activity for Cardiac Repair. J Am Heart Assoc 2019; 7:e009216. [PMID: 30371325 PMCID: PMC6404869 DOI: 10.1161/jaha.118.009216] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Prostaglandin E2 has long been known to be an immune modulator. It is released after tissue injury and plays a role in modulating macrophage activities, which are essential for tissue regeneration. However, the involvement of prostaglandin E2 receptor 2 (EP2)–dependent regulation of macrophages in postischemic heart is unclear. This study aims to evaluate the role of EP2 in damaged heart. Methods and Results The effect of EP2 in postischemic heart was evaluated using EP2‐deficient transgenic mice. We demonstrated that cardiac function was worse after myocardial injury on loss of EP2. Furthermore, EP2 deficiency also altered proinflammatory response and resulted in a defect in macrophage recruitment to the injured myocardium. Transcriptome analysis revealed that the expression of erythroid differentiation regulator 1 (Erdr1) was significantly induced in EP2‐deficient macrophages. Knocking down Erdr1 expression restored migration ability of EP2‐deficient cells both in vitro and in vivo. By using a genetic fate‐mapping approach, we showed that abolishment of EP2 expression effectively attenuated cell replenishment. Conclusions The EP2‐dependent signaling pathway plays a critical role in regulating macrophage recruitment to the injured myocardium, thereby exerting a function in modulating the inflammatory microenvironment for cardiac repair.
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Affiliation(s)
- Jasmine M F Wu
- 1 Institute of Basic Medical Sciences and Institute of Clinical Medicine National Cheng Kung University Tainan Taiwan.,2 Institute of Biomedical Sciences Academia Sinica Taipei Taiwan.,4 Leibniz Institute on Aging-Fritz Lipmann Institute Jena Germany
| | - Yuan-Yuan Cheng
- 2 Institute of Biomedical Sciences Academia Sinica Taipei Taiwan
| | - Tony W H Tang
- 2 Institute of Biomedical Sciences Academia Sinica Taipei Taiwan
| | - Crystal Shih
- 2 Institute of Biomedical Sciences Academia Sinica Taipei Taiwan
| | - Jyh-Hong Chen
- 3 Division of Cardiology Department of Medicine College of Medicine China Medical University Taichung Taiwan
| | - Patrick C H Hsieh
- 1 Institute of Basic Medical Sciences and Institute of Clinical Medicine National Cheng Kung University Tainan Taiwan.,2 Institute of Biomedical Sciences Academia Sinica Taipei Taiwan
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20
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Maseda D, Ricciotti E, Crofford LJ. Prostaglandin regulation of T cell biology. Pharmacol Res 2019; 149:104456. [PMID: 31553935 DOI: 10.1016/j.phrs.2019.104456] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/06/2019] [Accepted: 09/13/2019] [Indexed: 12/26/2022]
Abstract
Prostaglandins (PG) are pleiotropic bioactive lipids involved in the control of many physiological processes, including key roles in regulating inflammation. This links PG to the modulation of the quality and magnitude of immune responses. T cells, as a core part of the immune system, respond readily to inflammatory cues from their environment, and express a diverse array of PG receptors that contribute to their function and phenotype. Here we put in context our knowledge about how PG affect T cell biology, and review advances that bring light into how specific T cell functions that have been newly discovered are modulated through PG. We will also comment on drugs that target PG metabolism and sensing, their effect on T cell function during disease, and we will finally discuss how we can design new approaches that modulate PG in order to maximize desired therapeutic T cell effects.
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Affiliation(s)
- Damian Maseda
- Department of Microbiology, University of Pennsylvania School of Medicine, 8-138 Smillow Center for Translational Research, Philadelphia, PA, USA.
| | - Emanuela Ricciotti
- Department of Systems Pharmacology and Translational Therapeutics, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, USA
| | - Leslie J Crofford
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
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21
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Tait Wojno ED, Hunter CA, Stumhofer JS. The Immunobiology of the Interleukin-12 Family: Room for Discovery. Immunity 2019; 50:851-870. [PMID: 30995503 PMCID: PMC6472917 DOI: 10.1016/j.immuni.2019.03.011] [Citation(s) in RCA: 301] [Impact Index Per Article: 50.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/08/2019] [Accepted: 03/14/2019] [Indexed: 12/12/2022]
Abstract
The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.
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Affiliation(s)
- Elia D Tait Wojno
- Baker Institute for Animal Health and Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, 235 Hungerford Hill Rd., Ithaca, NY 14853, USA
| | - Christopher A Hunter
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 380 South University Ave., Philadelphia, PA 19104-4539, USA.
| | - Jason S Stumhofer
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205, USA.
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22
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Moschen AR, Tilg H, Raine T. IL-12, IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting. Nat Rev Gastroenterol Hepatol 2019; 16:185-196. [PMID: 30478416 DOI: 10.1038/s41575-018-0084-8] [Citation(s) in RCA: 304] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
IL-12 and IL-23 are closely related cytokines with important roles in the regulation of tissue inflammation. Converging evidence from studies in mice, human observational studies and population genetics supports the importance of these cytokines in the regulation of mucosal inflammation in the gut in particular. Ustekinumab, a therapeutic antibody targeting both cytokines is now widely licensed for the treatment of Crohn's disease, including in Europe, the USA, Canada and Japan, whilst agents targeting IL-23 specifically are in late-phase clinical trials. We review the emerging understanding of the biology of IL-12 and IL-23, as well as that of their major downstream cytokines, including IL-17. In particular, we discuss how their biology has influenced the development of clinical trials and therapeutic strategies in IBD, as well as how findings from clinical trials, at times surprising, have in turn refocused our understanding of the underlying biology.
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Affiliation(s)
- Alexander R Moschen
- Christian Doppler Laboratory for Mucosal Immunology, Medical University Innsbruck, Innsbruck, Austria. .,Department of Medicine, Division of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria.
| | - Herbert Tilg
- Department of Medicine, Division of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria
| | - Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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23
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Jia XY, Chang Y, Sun XJ, Wei F, Wu YJ, Dai X, Xu S, Wu HX, Wang C, Yang XZ, Wei W. Regulatory effects of paeoniflorin-6'-O-benzene sulfonate (CP-25) on dendritic cells maturation and activation via PGE2-EP4 signaling in adjuvant-induced arthritic rats. Inflammopharmacology 2019; 27:997-1010. [PMID: 30771056 DOI: 10.1007/s10787-019-00575-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 02/05/2019] [Indexed: 12/31/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease. Dendritic cells (DCs) are one of the most powerful antigen-presenting cells, and they play an important role in RA pathogenesis. Prostaglandin E2 (PGE2) is a potent lipid mediator that can regulate the maturation and activation of DCs, but the molecular mechanisms have not been elucidated. In this study, both in vitro and in an RA rat model, we investigated the mechanisms involved by focusing on PGE2-mediated signaling and using a novel anti-inflammatory compound, paeoniflorin-6'-O-benzene sulfonate (CP-25). PGE2 combined with tumor necrosis factor-α promoted DC maturation and activation through EP4-cAMP signaling. Treatment with CP-25 increased the endocytic capacity of DCs induced by PGE2. CP-25 inhibited the potency of DCs induced by the EP4 receptor agonist, CAY10598, to stimulate allogeneic T cells. Consistent with these findings, the CAY10598-induced upregulation of DC surface activation markers and production of IL-23 was significantly inhibited by CP-25 in a concentration-dependent manner. In vivo administration of CP-25 alleviated adjuvant arthritis (AA) in rats through inhibition of DC maturation and activation. Our results indicate that PGE2-EP4-cAMP signal hyperfunction can lead to abnormal activation of DC functions, which correlates with the course of disease in AA rats and provides a possible treatment target. The inhibition of DC maturation and activation by CP-25 interference of the PGE2-EP4 pathway may significantly contribute to the immunoregulatory profile of CP-25 when used to treat RA and other immune cell-mediated disorders.
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MESH Headings
- Adjuvants, Immunologic/adverse effects
- Adjuvants, Pharmaceutic/adverse effects
- Animals
- Arthritis, Experimental/chemically induced
- Arthritis, Experimental/drug therapy
- Arthritis, Experimental/metabolism
- Arthritis, Rheumatoid/chemically induced
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/metabolism
- Cyclic AMP/metabolism
- Dendritic Cells/drug effects
- Dendritic Cells/metabolism
- Dinoprostone/metabolism
- Glucosides/pharmacology
- Male
- Monoterpenes/pharmacology
- Rats
- Rats, Sprague-Dawley
- Receptors, Prostaglandin E, EP4 Subtype/metabolism
- Signal Transduction/drug effects
- Tumor Necrosis Factor-alpha/metabolism
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Affiliation(s)
- Xiao-Yi Jia
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Yan Chang
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China
| | - Xiao-Jing Sun
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China
| | - Fang Wei
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China
| | - Yu-Jing Wu
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China
| | - Xing Dai
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China
| | - Shu Xu
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China
| | - Hua-Xun Wu
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China
| | - Chun Wang
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China
| | - Xue-Zhi Yang
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China.
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24
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Yao C, Narumiya S. Prostaglandin-cytokine crosstalk in chronic inflammation. Br J Pharmacol 2019; 176:337-354. [PMID: 30381825 PMCID: PMC6329627 DOI: 10.1111/bph.14530] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 10/13/2018] [Accepted: 10/17/2018] [Indexed: 12/28/2022] Open
Abstract
Chronic inflammation underlies various debilitating disorders including autoimmune, neurodegenerative, vascular and metabolic diseases as well as cancer, where aberrant activation of the innate and acquired immune systems is frequently seen. Since non-steroidal anti-inflammatory drugs exert their effects by inhibiting COX and suppressing PG biosynthesis, PGs have been traditionally thought to function mostly as mediators of acute inflammation. However, an inducible COX isoform, COX-2, is often highly expressed in tissues of the chronic disorders, suggesting an as yet unidentified role of PGs in chronic inflammation. Recent studies have shown that in addition to their short-lived actions in acute inflammation, PGs crosstalk with cytokines and amplify the cytokine actions on various types of inflammatory cells and drive pathogenic conversion of these cells by critically regulating their gene expression. One mode of such PG-mediated amplification is to induce the expression of relevant cytokine receptors, which is typically observed in Th1 cell differentiation and Th17 cell expansion, events leading to chronic immune inflammation. Another mode of amplification is cooperation of PGs with cytokines at the transcription level. Typically, PGs and cytokines synergistically activate NF-κB to induce the expression of inflammation-related genes, one being COX-2 itself, which makes PG-mediated positive feedback loops. This signalling consequently enhances the expression of various NF-κB-induced genes including chemokines to macrophages and neutrophils, which enables sustained infiltration of these cells and further amplifies chronic inflammation. In addition, PGs are also involved in tissue remodelling such as fibrosis and angiogenesis. In this article, we review these findings and discuss their relevance to human diseases.
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Affiliation(s)
- Chengcan Yao
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Shuh Narumiya
- Alliance Laboratory for Advanced Medical Research and Department of Drug Discovery Medicine, Medical Innovation CenterKyoto University Graduate School of MedicineKyotoJapan
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25
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Impact of Brucellosis on Interleukin -23 Level, Acid Phosphates and Some Other Trace Elements. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2018. [DOI: 10.22207/jpam.12.4.37] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Wang Y, Han CC, Cui D, Luo TT, Li Y, Zhang Y, Ma Y, Wei W. Immunomodulatory Effects of CP-25 on Splenic T Cells of Rats with Adjuvant Arthritis. Inflammation 2018; 41:1049-1063. [PMID: 29473135 DOI: 10.1007/s10753-018-0757-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease in which T cells play an important role. Paeoniflorin-6-oxy-benzenesulfonate (CP-25) shows a strong anti-inflammatory and immunomodulatory effect in the joint of adjuvant arthritis (AA) rats, but the role of the spleen function is still unclear. The aim of this study was to research how CP-25 regulated spleen function of AA rats. Male Sprague-Dawley rats were administered with CP-25 (50 mg/kg) orally from day 17 to 29 after immunization. The spleen histopathological changes were analyzed by hematoxylin-eosin staining. G protein-coupled receptor kinases (GRKs) and prostaglandin receptor subtypes (EPs) were screened by Western blot and immunohistochemistry. The co-expression of GRK2 and EP2 as well as GRK2 and EP4 was measured by immunofluorescence and co-immunoprecipitation. The expression of GRK2 and EP4 in splenic T cells was further detected by immunofluorescence. CP-25 was found to relieve the secondary paw swelling, attenuate histopathologic changes, and downregulate GRK2, EP2 and EP4 expression in AA rats. Additionally, CP-25 not only downregulated the co-expression of GRK2 and EP4 but also downregulated GRK2, EP4 expression in splenic T cells of AA rats. From these results, we can infer that CP-25 play an anti-inflammatory and immune function by affecting the function of the splenic T cells.
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Affiliation(s)
- Yang Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei, 230032, China
| | - Chen-Chen Han
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei, 230032, China
| | - Dongqian Cui
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei, 230032, China
| | - Ting-Ting Luo
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei, 230032, China
| | - Yifan Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei, 230032, China
| | - Yuwen Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei, 230032, China
| | - Yang Ma
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei, 230032, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Meishan Road 81, Hefei, 230032, China.
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Debeuf N, Lambrecht BN. Eicosanoid Control Over Antigen Presenting Cells in Asthma. Front Immunol 2018; 9:2006. [PMID: 30233591 PMCID: PMC6131302 DOI: 10.3389/fimmu.2018.02006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 08/14/2018] [Indexed: 12/11/2022] Open
Abstract
Asthma is a common lung disease affecting 300 million people worldwide. Allergic asthma is recognized as a prototypical Th2 disorder, orchestrated by an aberrant adaptive CD4+ T helper (Th2/Th17) cell immune response against airborne allergens, that leads to eosinophilic inflammation, reversible bronchoconstriction, and mucus overproduction. Other forms of asthma are controlled by an eosinophil-rich innate ILC2 response driven by epithelial damage, whereas in some patients with more neutrophilia, the disease is driven by Th17 cells. Dendritic cells (DCs) and macrophages are crucial regulators of type 2 immunity in asthma. Numerous lipid mediators including the eicosanoids prostaglandins and leukotrienes influence key functions of these cells, leading to either pro- or anti-inflammatory effects on disease outcome. In this review, we will discuss how eicosanoids affect the functions of DCs and macrophages in the asthmatic lung and how this leads to aberrant T cell differentiation that causes disease.
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Affiliation(s)
- Nincy Debeuf
- Laboratory of Immunoregulation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.,Department of Internal Medicine, Ghent University, Ghent, Belgium
| | - Bart N Lambrecht
- Laboratory of Immunoregulation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.,Department of Internal Medicine, Ghent University, Ghent, Belgium.,Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, Netherlands
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28
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Zhang J, Zhang Z, Zhang W, Li X, Wu T, Li T, Cai M, Yu Z, Xiang J, Cai D. Jia-Jian-Di-Huang-Yin-Zi decoction exerts neuroprotective effects on dopaminergic neurons and their microenvironment. Sci Rep 2018; 8:9886. [PMID: 29959371 PMCID: PMC6026152 DOI: 10.1038/s41598-018-27852-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 06/07/2018] [Indexed: 11/09/2022] Open
Abstract
As a classical prescription of Traditional Chinese medicine, the Jia-Jian-Di-Huang-Yin-Zi (JJDHYZ) decoction has long been used to treat movement disorders. The present study evaluated the effects of JJDHYZ on dopaminergic (DA) neurons and their survival-enhancing microenvironment as well as the possible mechanisms involved using a mouse model of Parkinson's disease. In MPTP-lesioned mice, a high dosage of JJDHYZ (34 g/kg/day) attenuated the loss of DA neurons, reversed the dopamine depletion, and improved the expression of glial-derived neurotrophic factor (GDNF) compared to the untreated model group. JJDHYZ also protected the ultrastructure of the blood-brain barrier (BBB) and tight junction proteins by inhibiting the activation of microglia and astrocytes besides the increase in three types of matrix metalloproteinases in the substantia nigra. In conclusion, the JJDHYZ-high dosage (JJDHYZ-H) group exhibited the neuroprotection of DA neurons, and the underlying mechanism may be related to the survival-enhancing microenvironment of the DA neurons.
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Affiliation(s)
- Jingsi Zhang
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhennian Zhang
- Department of Neurology, Nanjing Hospital of Traditional Chinese Medicine, Nanjing, 210000, China
| | - Wen Zhang
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiangting Li
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Ting Wu
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Tingting Li
- Department of Neurology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Min Cai
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Zhonghai Yu
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jun Xiang
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Dingfang Cai
- Department of Integrative Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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Samuels JS, Holland L, López M, Meyers K, Cumbie WG, McClain A, Ignatowicz A, Nelson D, Shashidharamurthy R. Prostaglandin E2 and IL-23 interconnects STAT3 and RoRγ pathways to initiate Th17 CD4 + T-cell development during rheumatoid arthritis. Inflamm Res 2018; 67:589-596. [PMID: 29713730 DOI: 10.1007/s00011-018-1153-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 04/16/2018] [Accepted: 04/23/2018] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The chronic inflammation associated with rheumatoid arthritis (RA) leads to focal and systemic bone erosion of the joints resulting in a crippling disability. Recent reports indicate an increase in the incidence of RA in the coming years, placing a significant burden on healthcare resources. The incidence of RA is observed to be increasing with age and a significant proportion of those new cases will be aggressively erosive. FINDINGS The altered physiology, due to immune disturbances, contributes towards RA pathogenesis. The imbalance of inflammatory cytokines and non-cytokine immune modulators such as prostaglandin E2 (PGE2) and IL-23-induced pathogenic IL-17, plays a crucial role in persistent inflammation and bone degradation during RA. However, the molecular mechanism of IL-23, a key cytokine, and PGE2 in the development and perpetuation of IL-17 producing effector Th17 cells is poorly understood. CONCLUSION This review focuses on research findings that provide insight into the contribution of PGE2 and IL-23 during the development of pathogenic Th17 cells. We also highlight the key transcriptional factors required for Th17 development and therapeutic strategies to disrupt the interaction between IL-23 and IL-17 to prevent the end-organ damage in RA.
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Affiliation(s)
- Janaiya S Samuels
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Lauren Holland
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - María López
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Keya Meyers
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - William G Cumbie
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Anna McClain
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Aleksandra Ignatowicz
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Daryllynn Nelson
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA
| | - Rangaiah Shashidharamurthy
- Department of Pharmaceutical Sciences, School of Pharmacy, Philadelphia College of Osteopathic Medicine-Georgia Campus, Room 3031, 625 Old Peachtree Road, NW, Suwanee, GA, 30024, USA.
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30
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Chang LL, Hsu WH, Kao MC, Chou CC, Lin CC, Liu CJ, Weng BC, Kuo FC, Kuo CH, Lin MH, Wang CJ, Lin CH, Wu DC, Huang SK. Stromal C-type lectin receptor COLEC12 integrates H. pylori, PGE2-EP2/4 axis and innate immunity in gastric diseases. Sci Rep 2018; 8:3821. [PMID: 29491476 PMCID: PMC5830506 DOI: 10.1038/s41598-018-20957-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 01/17/2018] [Indexed: 12/12/2022] Open
Abstract
Tissue stroma is known to be important in regulating Hp-mediated inflammation, but its interaction with Hp and dendritic cells (DCs) remains to be determined. To this end, the potential crosstalk between H. pylori (Hp) infected gastric stromal cells (Hp-GSCs) and DCs was investigated. Primary GSCs from cancerous and adjacent normal tissues were generated from gastric cancer patients, and monocyte-derived DCs were obtained from healthy individuals. Levels of cytokines and prostaglandin E2 (PGE2) were measured by ELISA, and C-type lectin expression in GSCs was assessed by flow cytometry and immunohistochemistry. In a trans-well co-culture system, significantly upregulated DC-derived IL-23 expression was found when DCs were co-cultured with Hp-infected GSCs (Hp-GSCs). Further, PGE2 from Hp-GSCs was discovered to possess the priming effect, which could be inhibited by anti-COLEC12 (Collectin subfamily member 12) Abs, COLEC12 knockdown or when alpha3-fucosyltransferase-null (futB; HP0651) strain of Hp was used. Also, the expression of COLEC12 was co-localized with CD90+ stromal cells in cancerous tissues. Hp-GSCs-conditioned DCs were able to induce the expression of IL-17 from CD4+ T cells, which could be inhibited by IL-23-neutralizing Abs. These results suggested the importance of COLEC12 as a receptor involved in Hp-stromal cell interaction and its subsequent conditioning effect on DCs.
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Affiliation(s)
- Lin-Li Chang
- Department of Microbiology and Immunology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Wen-Hung Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Mou-Chieh Kao
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.,Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Chih-Chung Chou
- Department of Microbiology and Immunology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Cheng Lin
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Jung Liu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Bi-Chuang Weng
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Fu-Chen Kuo
- School of Medicine, College of Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Chao-Hung Kuo
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Hong Lin
- Department of Microbiology and Immunology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chun-Jen Wang
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Chun-Hung Lin
- Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program and the Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.,Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.,Department of Chemistry, National Taiwan University, Taipei, Taiwan
| | - Deng-Chyang Wu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. .,Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
| | - Shau-Ku Huang
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, 35053, Taiwan. .,Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. .,Shen-Zhen University Lo-Hu Hospital, Shen-Zhen, China. .,Johns Hopkins Asthma and Allergy Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21224, USA.
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31
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Maseda D, Johnson EM, Nyhoff LE, Baron B, Kojima F, Wilhelm AJ, Ward MR, Woodward JG, Brand DD, Crofford LJ. mPGES1-Dependent Prostaglandin E 2 (PGE 2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE 2 Production. THE JOURNAL OF IMMUNOLOGY 2017; 200:725-736. [PMID: 29237778 DOI: 10.4049/jimmunol.1601808] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 11/06/2017] [Indexed: 01/24/2023]
Abstract
The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE2, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE2 levels and is highly expressed at sites of inflammation. PGE2 is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen-CFA immunization response, lack of mPGES1 impaired the numbers of CD4+ regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1-/- CD4+ cells showed impaired IL-17A, IFN-γ, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE2 by cocultured APCs synergized with that of Ag-experienced CD4+ T cells, with mPGES1 competence in the APC compartment enhancing CD4+ IL-17A and IFN-γ responses. However, in contrast with CD4+ cells that were Ag primed in vivo, exogenous PGE2 inhibited proliferation and skewed IL-17A to IFN-γ production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE2 production that impacts effector T cell IL-17A and IFN-γ responses.
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Affiliation(s)
- Damian Maseda
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202
| | - Elizabeth M Johnson
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202
| | - Lindsay E Nyhoff
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202
| | - Bridgette Baron
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202
| | - Fumiaki Kojima
- Department of Pharmacology, Kitasato University, Tokyo 108-8641, Japan
| | - Ashley J Wilhelm
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202
| | - Martin R Ward
- University of Kentucky Medical Center, Lexington, KY 40536; and
| | | | - David D Brand
- Division of Rheumatology, University of Tennessee, Memphis, TN 38104
| | - Leslie J Crofford
- Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37202;
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The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis. Viruses 2017; 9:v9100303. [PMID: 29048384 PMCID: PMC5691654 DOI: 10.3390/v9100303] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 10/11/2017] [Accepted: 10/13/2017] [Indexed: 12/12/2022] Open
Abstract
The T helper 17 (Th17) cells represent a subset of CD4+ T-cells with unique effector functions, developmental plasticity, and stem-cell features. Th17 cells bridge innate and adaptive immunity against fungal and bacterial infections at skin and mucosal barrier surfaces. Although Th17 cells have been extensively studied in the context of autoimmunity, their role in various other pathologies is underexplored and remains an area of open investigation. This review summarizes the history of Th17 cell discovery and the current knowledge relative to the beneficial role of Th17 cells in maintaining mucosal immunity homeostasis. We further discuss the concept of Th17 pathogenicity in the context of autoimmunity, cancer, and HIV infection, and we review the most recent discoveries on molecular mechanisms regulating HIV replication/persistence in pathogenic Th17 cells. Finally, we stress the need for novel fundamental research discovery-based Th17-specific therapeutic interventions to treat pathogenic conditions associated with Th17 abnormalities, including HIV infection.
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33
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Hooper KM, Kong W, Ganea D. Prostaglandin E2 inhibits Tr1 cell differentiation through suppression of c-Maf. PLoS One 2017; 12:e0179184. [PMID: 28604806 PMCID: PMC5467903 DOI: 10.1371/journal.pone.0179184] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 05/07/2017] [Indexed: 12/30/2022] Open
Abstract
Prostaglandin E2 (PGE2), a major lipid mediator abundant at inflammatory sites, acts as a proinflammatory agent in models of inflammatory/autoimmune diseases by promoting CD4 Th1/Th17 differentiation. Regulatory T cells, including the IL-10 producing Tr1 cells counterbalance the proinflammatory activity of effector Th1/Th17 cells. Tr1 cell differentiation and function are induced by IL-27, and depend primarily on sustained expression of c-Maf in addition to AhR and Blimp-1. In agreement with the in vivo proinflammatory role of PGE2, here we report for the first time that PGE2 inhibits IL-27-induced differentiation and IL-10 production of murine CD4+CD49b+LAG-3+Foxp3- Tr1 cells. The inhibitory effect of PGE2 was mediated through EP4 receptors and induction of cAMP, leading to a significant reduction in c-Maf expression. Although PGE2 reduced IL-21 production in differentiating Tr1 cells, its inhibitory effect on Tr1 differentiation and c-Maf expression also occurred independent of IL-21 signaling. PGE2 did not affect STAT1/3 activation, AhR expression and only marginally reduced Egr-2/Blimp-1 expression. The effect of PGE2 on CD4+CD49b+LAG-3+ Tr1 differentiation was not associated with either induction of Foxp3 or IL-17 production, suggesting a lack of transdifferentiation into Foxp3+ Treg or effector Th17 cells. We recently reported that PGE2 inhibits the expression and production of IL-27 from activated conventional dendritic cells (cDC) in vivo and in vitro. The present study indicates that PGE2 also reduces murine Tr1 differentiation and function directly by acting on IL-27-differentiating Tr1 cells. Together, the ability of PGE2 to inhibit IL-27 production by cDC, and the direct inhibitory effect on Tr1 differentiation mediated through reduction in c-Maf expression, represent a new mechanistic perspective for the proinflammatory activity of PGE2.
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Affiliation(s)
- Kirsten Mary Hooper
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
| | - Weimin Kong
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
| | - Doina Ganea
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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34
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Hooper KM, Yen JH, Kong W, Rahbari KM, Kuo PC, Gamero AM, Ganea D. Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1. THE JOURNAL OF IMMUNOLOGY 2017; 198:1521-1530. [PMID: 28062696 DOI: 10.4049/jimmunol.1601073] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 12/09/2016] [Indexed: 12/20/2022]
Abstract
IL-27, a multifunctional cytokine produced by APCs, antagonizes inflammation by affecting conventional dendritic cells (cDC), inducing IL-10, and promoting development of regulatory Tr1 cells. Although the mechanisms involved in IL-27 induction are well studied, much less is known about the factors that negatively impact IL-27 expression. PGE2, a major immunomodulatory prostanoid, acts as a proinflammatory agent in several models of inflammatory/autoimmune disease, promoting primarily Th17 development and function. In this study, we report on a novel mechanism that promotes the proinflammatory function of PGE2 We showed previously that PGE2 inhibits IL-27 production in murine bone marrow-derived DCs. In this study, we show that, in addition to bone marrow-derived DCs, PGE2 inhibits IL-27 production in macrophages and in splenic cDC, and we identify a novel pathway consisting of signaling through EP2/EP4→induction of cAMP→downregulation of IFN regulatory factor 1 expression and binding to the p28 IFN-stimulated response element site. The inhibitory effect of PGE2 on p28 and irf1 expression does not involve endogenous IFN-β, STAT1, or STAT2, and inhibition of IL-27 does not appear to be mediated through PKA, exchange protein activated by cAMP, PI3K, or MAPKs. We observed similar inhibition of il27p28 expression in vivo in splenic DC following administration of dimethyl PGE2 in conjunction with LPS. Based on the anti-inflammatory role of IL-27 in cDC and through the generation of Tr1 cells, we propose that the PGE2-induced inhibition of IL-27 in activated cDC represents an important additional mechanism for its in vivo proinflammatory functions.
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Affiliation(s)
- Kirsten M Hooper
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
| | - Jui-Hung Yen
- Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN 46202
| | - Weimin Kong
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
| | - Kate M Rahbari
- Department of Microbiology and Immunology, University of Illinois College of Medicine at Chicago, Chicago, IL 60612; and
| | - Ping-Chang Kuo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Fort Wayne, IN 46202
| | - Ana M Gamero
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
| | - Doina Ganea
- Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
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35
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Poland M, Ten Klooster JP, Wang Z, Pieters R, Boekschoten M, Witkamp R, Meijerink J. Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23-IL-17 signaling in macrophages. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1861:2020-2028. [PMID: 27663185 DOI: 10.1016/j.bbalip.2016.09.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 08/24/2016] [Accepted: 09/16/2016] [Indexed: 01/01/2023]
Abstract
Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100-500nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.
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Affiliation(s)
- Mieke Poland
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Jean Paul Ten Klooster
- Institute for Life Sciences & Chemistry, Utrecht University of Applied Sciences, Utrecht, The Netherlands.
| | - Zheng Wang
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Raymond Pieters
- Institute for Life Sciences & Chemistry, Utrecht University of Applied Sciences, Utrecht, The Netherlands.
| | - Mark Boekschoten
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Renger Witkamp
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
| | - Jocelijn Meijerink
- Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands.
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Koga H, Recke A, Vidarsson G, Pas HH, Jonkman MF, Hashimoto T, Kasprick A, Ghorbanalipoor S, Tenor H, Zillikens D, Ludwig RJ. PDE4 Inhibition as Potential Treatment of Epidermolysis Bullosa Acquisita. J Invest Dermatol 2016; 136:2211-2220. [DOI: 10.1016/j.jid.2016.06.619] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 06/05/2016] [Accepted: 06/13/2016] [Indexed: 12/20/2022]
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Bone marrow transplantation alters lung antigen-presenting cells to promote TH17 response and the development of pneumonitis and fibrosis following gammaherpesvirus infection. Mucosal Immunol 2016; 9:610-20. [PMID: 26376362 PMCID: PMC4794430 DOI: 10.1038/mi.2015.85] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 07/31/2015] [Indexed: 02/04/2023]
Abstract
Hematopoietic stem cell transplantation (HSCT) efficacy is limited by numerous pulmonary complications. We developed a model of syngeneic bone marrow transplantion (BMT) followed by infection with murine gamma herpesvirus-68 that results in pneumonitis and fibrosis and mimics human "noninfectious" HSCT complications. BMT mice experience increased early lytic replication, but establish viral latency by 21 days post infection. CD4 T cells in BMT mice are skewed toward interleukin (IL)-17A rather than interferon (IFN)-γ production. Transplantation of bone marrow from Il-17a(-/-) donors or treatment with anti-IL-17A neutralization antibodies at late stages attenuates pneumonitis and fibrosis in infected BMT mice, suggesting that hematopoietic-derived IL-17A is essential for development of pathology. IL-17A directly influences activation and extracellular matrix production by lung mesenchymal cells. Lung CD11c+ cells of BMT mice secrete more transforming growth factor beta-β1, and pro-TH17 mRNAs for IL-23 and IL-6, and less TH1-promoting cytokine mRNA for IFN-γ but slightly more IL-12 mRNA in response to viral infection. Adoptive transfer of non-BMT lung CD11c-enriched cells restores robust TH1 response and suppresses aberrant TH17 response in BMT mice to improve lung pathology. Our data suggest that "noninfectious" HSCT lung complications may reflect preceding viral infections and demonstrate that IL-17A neutralization may offer therapeutic advantage even after disease onset.
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The phosphodiesterase 4 inhibitor roflumilast augments the Th17-promoting capability of dendritic cells by enhancing IL-23 production, and impairs their T cell stimulatory activity due to elevated IL-10. Int Immunopharmacol 2016; 35:174-184. [PMID: 27070502 DOI: 10.1016/j.intimp.2016.03.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 03/15/2016] [Accepted: 03/18/2016] [Indexed: 11/20/2022]
Abstract
Phosphodiesterase 4 (PDE4) inhibitors serve to prevent degradation of the intracellular second messenger cAMP, resulting in broad anti-inflammatory effects on different cell types including immune cells. Agents that elevate cAMP levels via activation of adenylate cyclase have been shown to imprint a Th17-promoting capacity in dendritic cells (DCs). Therefore, we studied the potential of therapeutically relevant PDE inhibitors to induce a pronounced Th17-skewing capacity in DCs. Here we show that mouse bone marrow-derived (BM-) DCs when treated with the PDE4 inhibitor roflumilast (ROF, trade name: Daxas) in the course of stimulation with LPS (ROF-DCs) evoked elevated IL-17 levels in cocultured allogeneic T cells. In addition, as compared with control settings, levels of IFN-γ remained unaltered, while contents of Th2 cytokines (IL-5, IL-10) were diminished. ROF enhanced expression of the Th17-promoting factor IL-23 in BM-DCs. In line, neutralizing antibodies specific for IL-23 or IL-6 when applied to DC/T cell cocultures partially inhibited the IL17-promoting effect of ROF-DCs. Furthermore, ROF-DCs displayed a markedly diminished allogeneic T cell stimulatory capacity due to enhanced production of IL-10, which was restored upon application of IL-10 specific neutralizing antibody to DC/T cell cocultures. Both the IL-17-inducing and impaired T cell stimulatory capacity of BM-DCs were mimicked by a specific activator of protein kinase A, while stimulation of EPACs (exchange proteins of activated cAMP) did not yield such effects. Taken together, our findings suggest that PDE4 inhibitors aside from their broad overall anti-inflammatory effects may enhance the Th17-polarizing capacity in DCs as an unwanted side effect.
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Malecka A, Wang Q, Shah S, Sutavani RV, Spendlove I, Ramage JM, Greensmith J, Franks HA, Gough MJ, Saalbach A, Patel PM, Jackson AM. Stromal fibroblasts support dendritic cells to maintain IL-23/Th17 responses after exposure to ionizing radiation. J Leukoc Biol 2016; 100:381-9. [PMID: 27049023 PMCID: PMC4945355 DOI: 10.1189/jlb.3a1015-474r] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 03/18/2016] [Indexed: 12/30/2022] Open
Abstract
Cross talk between DCs and FBs in understanding the effects of IR in DC function. Dendritic cell function is modulated by stromal cells, including fibroblasts. Although poorly understood, the signals delivered through this crosstalk substantially alter dendritic cell biology. This is well illustrated with release of TNF-α/IL-1β from activated dendritic cells, promoting PGE2 secretion from stromal fibroblasts. This instructs dendritic cells to up-regulate IL-23, a key Th17-polarizing cytokine. We previously showed that ionizing radiation inhibited IL-23 production by human dendritic cells in vitro. In the present study, we investigated the hypothesis that dendritic cell-fibroblast crosstalk overcomes the suppressive effect of ionizing radiation to support appropriately polarized Th17 responses. Radiation (1–6 Gy) markedly suppressed IL-23 secretion by activated dendritic cells (P < 0.0001) without adversely impacting their viability and consequently, inhibited the generation of Th17 responses. Cytokine suppression by ionizing radiation was selective, as there was no effect on IL-1β, -6, -10, and -27 or TNF-α and only a modest (11%) decrease in IL-12p70 secretion. Coculture with fibroblasts augmented IL-23 secretion by irradiated dendritic cells and increased Th17 responses. Importantly, in contrast to dendritic cells, irradiated fibroblasts maintained their capacity to respond to TNF-α/IL-1β and produce PGE2, thus providing the key intermediary signals for successful dendritic cell-fibroblasts crosstalk. In summary, stromal fibroblasts support Th17-polarizing cytokine production by dendritic cells that would otherwise be suppressed in an irradiated microenvironment. This has potential ramifications for understanding the immune response to local radiotherapy. These findings underscore the need to account for the impact of microenvironmental factors, including stromal cells, in understanding the control of immunity.
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Affiliation(s)
- Anna Malecka
- Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom
| | - Qunwei Wang
- Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom
| | - Sabaria Shah
- Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom
| | - Ruhcha V Sutavani
- Cancer Immunotherapy Group, Division of Cancer and Stem Cells, University of Nottingham, Nottingham, United Kingdom; Cell Signalling and Immunology, University of Dundee, Scotland, United Kingdom
| | - Ian Spendlove
- Cancer Immunotherapy Group, Division of Cancer and Stem Cells, University of Nottingham, Nottingham, United Kingdom
| | - Judith M Ramage
- Cancer Immunotherapy Group, Division of Cancer and Stem Cells, University of Nottingham, Nottingham, United Kingdom
| | - Julie Greensmith
- Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom; Intelligent Modelling and Analysis Research Group, University of Nottingham, Nottingham, United Kingdom
| | - Hester A Franks
- Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom
| | - Michael J Gough
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, Oregon, USA
| | - Anja Saalbach
- Klinik fur Dermatologie, University of Leipzig, Germany; and
| | - Poulam M Patel
- Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom
| | - Andrew M Jackson
- Host-Tumour Interactions Group, University of Nottingham, Nottingham, United Kingdom;
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Lai Y, Dong C. Therapeutic antibodies that target inflammatory cytokines in autoimmune diseases. Int Immunol 2016; 28:181-8. [PMID: 26545932 PMCID: PMC4889878 DOI: 10.1093/intimm/dxv063] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 10/18/2015] [Indexed: 12/13/2022] Open
Abstract
Inflammatory cytokines are key regulators of immune responses. Persistent and excessive production of inflammatory cytokines underscores the development of autoimmune diseases. Therefore, neutralizing inflammatory cytokines or antagonizing their receptor function is considered as a useful therapeutic strategy to treat autoimmune diseases. To achieve the success of such a strategy, understanding of the complex actions of these cytokines and cytokine networks is required. In this review we focus on four inflammatory cytokines--tumor necrosis factor α (TNFα), interleukin-6 (IL-6), IL-23 and IL-17--and dissect how the dysregulation of these cytokines regulates autoimmune diseases. On the basis of pre-clinical and clinical data, we specifically discuss the therapeutic rationale for targeting these cytokines and describe the potential adverse effects.
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Affiliation(s)
- Yuping Lai
- Shanghai Key Laboratory of Regulatory Biology, School of Life Science, East China Normal University, No.500 Minhang Dongchuan Road, Shanghai 200241, China
| | - Chen Dong
- Institute for Immunology, Tsinghua University, Medical Research Building D330, No.30 Haidian Shuangqing Road, Beijing 100084, China
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Evaluation of Chosen Cytokine Levels among Patients with Herpes Zoster as Ability to Provide Immune Response. PLoS One 2016; 11:e0150301. [PMID: 26934574 PMCID: PMC4775057 DOI: 10.1371/journal.pone.0150301] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 02/03/2016] [Indexed: 12/22/2022] Open
Abstract
Aim and Background Herpes zoster is a viral disease caused by the reactivation of varicella–zoster virus (VZV) which remained latent in the cranial nerve or dorsal root ganglia. Cell-mediated immunity is known to decline with age as part of immunosenescence and can lead to the reactivation of VZV. Whereas herpes zoster is usually mild in healthy young persons, older patients are at increased risk for complications. In the present study we investigated the serum cytokine profile (IL-17, IL-23, IL-21, IL-4, IL-12), representing cellular and humoral immunity and assessed the level of VZV IgG antibodies in patients with herpes zoster. Methods We investigated the serum concentrations of IL-17, IL-23, IL-21, IL-4, IL-12 and the level of VZV IgG antibodies in 23 patients with herpes zoster who did not develop superinfection. The control group was represented by 21 individuals in similar age with no inflammatory and infectious diseases. Cytokine and antibodies levels were measured by ELISA method. Statistical analysis was performed using the ROC curve (receiver operating characteristic), t-test, Welch’s t-test, and nonparametric tests with STATISTICA 10 software. Results In patients with herpes zoster, the serum level of IL-17, IL-23, IL-21, IL-4 and IL-12 as well as VZV IgG antibodies titer were statistically significantly increased compared to control group. Conclusion Our results confirm the broad activation of the immune system involving humoral and cell-mediated immunity.
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Lipid mediators of inflammation in rheumatoid arthritis and osteoarthritis. Best Pract Res Clin Rheumatol 2015; 29:741-55. [DOI: 10.1016/j.berh.2016.02.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Tuncer S, Banerjee S. Eicosanoid pathway in colorectal cancer: Recent updates. World J Gastroenterol 2015; 21:11748-11766. [PMID: 26557000 PMCID: PMC4631974 DOI: 10.3748/wjg.v21.i41.11748] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/25/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Enzymatic metabolism of the 20C polyunsaturated fatty acid (PUFA) arachidonic acid (AA) occurs via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer (CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.
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PGE2 Elevates IL-23 Production in Human Dendritic Cells via a cAMP Dependent Pathway. Mediators Inflamm 2015; 2015:984690. [PMID: 26412948 PMCID: PMC4564649 DOI: 10.1155/2015/984690] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 08/03/2015] [Accepted: 08/16/2015] [Indexed: 12/28/2022] Open
Abstract
PGE2 elevates IL-23 production in mouse dendritic cells while inhibits IL-23 production in isolated human monocytes. Whether this differential effect of PGE2 on IL-23 production is cell-type- or species-specific has not been investigated in detail. The present study was designed to investigate the effect of PGE2 on IL-23 production in human DCs and the possible underlying mechanisms. Human monocytes derived dendritic cells (Mo-DCs) were pretreated with or without PGE2. Then the cells were incubated with zymosan. Our results demonstrated that PGE2 promoted zymosan-induced IL-23 production in a concentration dependent manner. In addition, it was found that PGE2 is also able to elevate MyD88-mediated IL-23 p19 promoter activity. More importantly, ELISA data demonstrated that db-cAMP, a cAMP analog, and forskolin, an adenylate cyclase activator, can mimic the effect of PGE2 on zymosan-induced IL-23 production, and rp-cAMP, a protein kinase A (PKA) inhibitor, can block the effect of PGE2. Moreover, PGE2 can increase zymosan-induced expression of the mRNA levels of both p19 and p40 subunits, which was mimicked by db-cAMP and forskolin. Our data suggest that PGE2 elevates the production of IL-23 in human Mo-DCs via a cAMP dependent pathway.
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Prostaglandin E2-EP4 signaling persistently amplifies CD40-mediated induction of IL-23 p19 expression through canonical and non-canonical NF-κB pathways. Cell Mol Immunol 2015; 13:240-50. [PMID: 26189370 DOI: 10.1038/cmi.2015.70] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 06/22/2015] [Accepted: 06/22/2015] [Indexed: 01/13/2023] Open
Abstract
While there is mounting evidence that interleukin (IL)-23-IL-17 axis plays a critical role in the pathogenesis of various autoimmune diseases, much remains to be elucidated on how IL-23 is induced in the pathological processes. IL-23 is a heterodimer composed of p19 and p40, the latter being shared with IL-12. We previously reported that prostaglandin (PG) E2 promotes CD40-mediated induction of Il23a (p19) expression through its E receptor subtype 4 (EP4) receptor in splenic dendritic cells (DCs). Here, we have analyzed signaling pathways regulating Il23a induction in the cross talk between EP4 and CD40 in bone marrow-derived DCs. We found that PGE2 synergistically induced Il23a transcription with CD40 signaling. An EP4 agonist, but not agonists of EP1, EP2, or EP3, reproduced this action. Stimulation of CD40 with an agonist antibody evoked biphasic induction of Il23a expression, with the early phase peaking at 1 h and the late phase peaking at 12 h and lasting up to 36 h after stimulation, whereas induction by lipopolysaccharide or tumor necrosis factor-α was transient. The early phase induction by CD40 stimulation was absent in DCs derived from Nfkb1-deficient mice, and the late phase induction was eliminated by RNA interference of nuclear factor-kappa B (NF-κB) p100 subunit. Further, cAMP response element-binding protein (CREB) depletion completely eliminated the induction of Il23a by CD40 stimulation. The addition of the EP4 agonist amplified the induction in both phases through the cAMP-protein kinase A (PKA) pathway. These results suggest that Il23a expression in DCs is synergistically triggered by the PG E2-EP4-cAMP-PKA pathway and canonical/non-canonical NF-κB pathways and CREB activated by CD40 stimulation.
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Teng MWL, Bowman EP, McElwee JJ, Smyth MJ, Casanova JL, Cooper AM, Cua DJ. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 2015; 21:719-29. [PMID: 26121196 DOI: 10.1038/nm.3895] [Citation(s) in RCA: 608] [Impact Index Per Article: 60.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 05/05/2015] [Indexed: 12/18/2022]
Abstract
The cytokine interleukin-12 (IL-12) was thought to have a central role in T cell-mediated responses in inflammation for more than a decade after it was first identified. Discovery of the cytokine IL-23, which shares a common p40 subunit with IL-12, prompted efforts to clarify the relative contribution of these two cytokines in immune regulation. Ustekinumab, a therapeutic agent targeting both cytokines, was recently approved to treat psoriasis and psoriatic arthritis, and related agents are in clinical testing for a variety of inflammatory disorders. Here we discuss the therapeutic rationale for targeting these cytokines, the unintended consequences for host defense and tumor surveillance and potential ways in which these therapies can be applied to treat additional immune disorders.
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Affiliation(s)
- Michele W L Teng
- 1] Cancer Immunoregulation and Immunotherapy and Immunology in Cancer and Infection Laboratories, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. [2] School of Medicine, University of Queensland, Herston, Queensland, Australia
| | | | | | - Mark J Smyth
- 1] Cancer Immunoregulation and Immunotherapy and Immunology in Cancer and Infection Laboratories, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. [2] School of Medicine, University of Queensland, Herston, Queensland, Australia
| | - Jean-Laurent Casanova
- 1] St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA. [2] Howard Hughes Medical Institute, New York, New York, USA. [3] Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France. [4] Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, Paris, France. [5] Paris Descartes University, Imagine Institute, Paris, France
| | | | - Daniel J Cua
- Merck Research Laboratories, Palo Alto, California, USA
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Rothe T, Gruber F, Uderhardt S, Ipseiz N, Rössner S, Oskolkova O, Blüml S, Leitinger N, Bicker W, Bochkov VN, Yamamoto M, Steinkasserer A, Schett G, Zinser E, Krönke G. 12/15-Lipoxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function. J Clin Invest 2015; 125:1944-54. [PMID: 25844901 DOI: 10.1172/jci78490] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 02/27/2015] [Indexed: 11/17/2022] Open
Abstract
DCs are able to undergo rapid maturation, which subsequently allows them to initiate and orchestrate T cell-driven immune responses. DC maturation must be tightly controlled in order to avoid random T cell activation and development of autoimmunity. Here, we determined that 12/15-lipoxygenase-meditated (12/15-LO-mediated) enzymatic lipid oxidation regulates DC activation and fine-tunes consecutive T cell responses. Specifically, 12/15-LO activity determined the DC activation threshold via generation of phospholipid oxidation products that induced an antioxidative response dependent on the transcription factor NRF2. Deletion of the 12/15-LO-encoding gene or pharmacologic inhibition of 12/15-LO in murine or human DCs accelerated maturation and shifted the cytokine profile, thereby favoring the differentiation of Th17 cells. Exposure of 12/15-LO-deficient DCs to 12/15-LO-derived oxidized phospholipids attenuated both DC activation and the development of Th17 cells. Analysis of lymphatic tissues from 12/15-LO-deficient mice confirmed enhanced maturation of DCs as well as an increased differentiation of Th17 cells. Moreover, experimental autoimmune encephalomyelitis in mice lacking 12/15-LO resulted in an exacerbated Th17-driven autoimmune disease. Together, our data reveal that 12/15-LO controls maturation of DCs and implicate enzymatic lipid oxidation in shaping the adaptive immune response.
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Dendritic cells subsets mediated immune response during Plasmodium berghei ANKA and Plasmodium yoelii infection. Cytokine 2015; 73:198-206. [PMID: 25792277 DOI: 10.1016/j.cyto.2015.02.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 02/24/2015] [Accepted: 02/26/2015] [Indexed: 02/07/2023]
Abstract
The roles of dendritic cells (DCs) in mediating immunity against Plasmodium infection have been extensively investigated, but immune response during pathogenesis of malaria is still poorly understood. In the present study, we compared the splenic DCs phenotype and function during P. berghei ANKA (PbA) or P. yoelii (P. yoelii) infection in Swiss mice. We observed that PbA-infected mice developed more myeloid and mature DCs capable of secreting IL-12, while P. yoelii-infected mice had more plasmacytoid and immature DCs secreting higher levels of IL-10. Expression of FoxP3, IL-17, TGF-β and IL-6 were also different between these two infections. Thus, these results suggest that the phenotypic and functional subsets of splenic DCs are key factors for regulating immune responses to PbA and P. yoelii infections.
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PGE2-induced IDO1 inhibits the capacity of fully mature DCs to elicit an in vitro antileukemic immune response. J Immunol Res 2015; 2015:253191. [PMID: 25815345 PMCID: PMC4357138 DOI: 10.1155/2015/253191] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 02/10/2015] [Indexed: 11/21/2022] Open
Abstract
In the last years, dendritic cells (DC) have been evaluated for antitumor vaccination.
Although DC-based vaccines have raised great expectations, their clinical translation has
been largely disappointing. For these results, several explanations have been proposed.
In particular, the concomitant expression by DCs of tolerogenic pathways, such as the
immunosuppressive agent indoleamine 2,3-dioxygenase-1 (IDO1), has been demonstrated.
The aim of this study is to evaluate both the stimulatory and the tolerogenic feature of
monocyte-derived DCs (Mo-DCs) after maturation with PGE2. In particular,
the role of IDO1 expression in PGE2-matured Mo-DCs has been
addressed. Here we show that PGE2, which is required for full maturation of
DCs, is one mediator of DC tolerance by enhancing IDO1. PGE2-mediated
expression of IDO1 results in the production of kynurenine, in the generation of Tregs, and in the inhibition of either the allogeneic or the autologous antigen-specific stimulatory capacity of DCs. When pulsed with leukemic lysates and matured with PGE2, DCs are impaired in the induction of IFN-γ secreting CD4+ and CD8+ T cells due to IDO1 upregulation. Moreover, the inhibition of IDO1 enhances the antileukemic response. Overall, these results point toward the use of IDO1 inhibitors to enhance the vaccination capacity of DCs, matured with PGE2.
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Abstract
Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, γδ T cells, NKT cells, and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has evolved rapidly since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues, including the intestines, lung, liver, kidney, thymus, pancreas, and skin. IL-22 primarily targets nonhematopoietic epithelial and stromal cells, where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function.
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