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Takahashi K, Yoshimatsu R, Kaida Y, Hasegawa T, Ohmori K. Toll-like receptor 2 activation induces C-C motif chemokine ligand 5 production in canine keratinocytes. Vet Dermatol 2025. [PMID: 39973011 DOI: 10.1111/vde.13330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/19/2024] [Revised: 12/23/2024] [Accepted: 01/27/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Toll-like receptor 2 (TLR2) in keratinocytes can be activated by Staphylococcus spp. that are frequently detected on the skin of dogs with atopic dermatitis (AD). C-C motif chemokine ligand 5 (CCL5) produced by keratinocytes has been considered to be involved in the pathogenesis of canine AD (cAD). However, whether TLR2 activation induces CCL5 production in canine keratinocytes remains unclear. HYPOTHESIS/OBJECTIVES To elucidate the effect of TLR2 agonists on CCL5 production in canine keratinocytes, possible synergy with interferon (IFN)-γ, interleukin (IL)-13 or IL-4 and underlying mechanisms. MATERIALS AND METHODS Canine progenitor epidermal keratinocyte (CPEK) cells were stimulated with TLR2 agonists with or without inhibitors of the TLR2 signalling pathway or IFN-γ, a T-helper (Th)1-type cytokine and/or IL-13 or IL-4, a Th2-type cytokine. CCL5 protein concentrations in the culture supernatant were measured by enzyme-linked immunosorbent assay. Additionally, TLR2 mRNA expression was measured by real-time PCR in CPEK cells stimulated with IFN-γ. RESULTS TLR2 agonists increased CCL5 production in CPEK cells. Inhibitors of the TLR2 signalling pathway suppressed CCL5 production. IFN-γ, but not IL-13 or IL-4, synergistically enhanced TLR2 agonist-induced CCL5 production. IFN-γ partially increased TLR2 mRNA expression in CPEK cells. CONCLUSIONS AND CLINICAL RELEVANCE TLR2 activation by Staphylococcus spp. may produce CCL5 in canine keratinocytes, thereby recruiting immune cells into the skin of dogs with AD. During the Th1-activated chronic phase of cAD, where TLR2 expression may be partially upregulated, Staphylococcus spp. may exacerbate skin inflammation. Further studies are warranted to determine the clinical significance and mechanisms of skin bacteria-mediated CCL5 production in keratinocytes.
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Affiliation(s)
- Kaho Takahashi
- Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
| | - Rina Yoshimatsu
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
| | - Yuzuki Kaida
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
| | - Takehiro Hasegawa
- Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
- Kugenuna-Kaigan Animal Hospital, Fujisawa, Kanagawa, Japan
| | - Keitaro Ohmori
- Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
- Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
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Zhao H, Zhang L, Du D, Mai L, Liu Y, Morigen M, Fan L. The RIG-I-like receptor signaling pathway triggered by Staphylococcus aureus promotes breast cancer metastasis. Int Immunopharmacol 2024; 142:113195. [PMID: 39303544 DOI: 10.1016/j.intimp.2024.113195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/30/2024] [Revised: 09/10/2024] [Accepted: 09/14/2024] [Indexed: 09/22/2024]
Abstract
Host microbes are increasingly recognized as key components in various types of cancer, although their exact impact remains unclear. This study investigated the functional significance of Staphylococcus aureus (S. aureus) in breast cancer tumorigenesis and progression. We found that S. aureus invasion resulted in a compromised DNA damage response process, as evidenced by the absence of G1-phase arrest and apoptosis in breast cells in the background of double strand breaks production and the activation of the ataxia-telangiectasia mutated (ATM)-p53 signaling pathway. The high-throughput mRNA sequencing, bioinformatics analysis and pharmacological studies revealed that S. aureus facilitates breast cell metastasis through the innate immune pathway, particularly in cancer cells. During metastasis, S. aureus initially induced the expression of RIG-I-like receptors (RIG-I in normal breast cells, RIG-I and MDA5 in breast cancer cells), which in turn activated NF-κB p65 expression. We further showed that NF-κB p65 activated the CCL5-CCR5 pathway, contributing to breast cell metastasis. Our study provides novel evidence that the innate immune system, triggered by bacterial infection, plays a role in bacterial-driven cancer metastasis.
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Affiliation(s)
- Haile Zhao
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, State Key Laboratory of Reproductive Regulation & Breeding of Grassland livestock, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, PR China
| | - Linzhe Zhang
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, State Key Laboratory of Reproductive Regulation & Breeding of Grassland livestock, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, PR China
| | - Dongdong Du
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, State Key Laboratory of Reproductive Regulation & Breeding of Grassland livestock, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, PR China
| | - Lisu Mai
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, State Key Laboratory of Reproductive Regulation & Breeding of Grassland livestock, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, PR China
| | - Yaping Liu
- Department of Gynecology and Obstetrics, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, PR China
| | - Morigen Morigen
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, State Key Laboratory of Reproductive Regulation & Breeding of Grassland livestock, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, PR China.
| | - Lifei Fan
- Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, State Key Laboratory of Reproductive Regulation & Breeding of Grassland livestock, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, PR China.
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Kwankaew P, Mahittikorn A, Mala W, Kotepui KU, Anabire NG, Wilairatana P, Kotepui M. Association between RANTES/CCL5 levels with Plasmodium infections and malaria severity: a systematic review. Malar J 2024; 23:335. [PMID: 39521981 PMCID: PMC11550525 DOI: 10.1186/s12936-024-05152-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/02/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Malaria continues to be a significant global health concern, and developing effective therapeutic strategies requires an understanding of the immune response to the disease. This systematic review synthesized the current body of research on the role of regulated on activation, normal T cell expressed and secreted (RANTES)-in the pathogenesis and disease severity of malaria. METHODS A systematic review protocol was registered with PROSPERO under the registration number CRD42024535822. The systematic review was conducted following PRISMA guidelines to identify studies examining RANTES levels in individuals infected with Plasmodium species. Searches were performed across multiple databases, including ProQuest, Journals@Ovid, Embase, Scopus, PubMed, and MEDLINE. Further searches were performed in Google Scholar. Quality assessment was done using the Joanna Briggs Institute (JBI) critical appraisal tools. Alterations in RANTES levels in patients with malaria were synthesized narratively. RESULTS A comprehensive search of major databases identified 22 studies meeting inclusion criteria, predominantly focusing on Plasmodium falciparum and Plasmodium vivax infections. RANTES levels were found to vary significantly across different severities of malaria, with several studies reporting lower levels in severe cases compared to non-malarial controls. However, inconsistencies were observed in the alterations of RANTES levels between severe and non-severe malaria cases. CONCLUSION Taken together, the finding of this systematic review underscore the complex regulation of RANTES in malaria pathophysiology. Future research should focus on longitudinal assessments to elucidate the dynamic role of RANTES throughout the course of malaria and recovery, to potentially inform the design of novel therapeutic strategies.
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Affiliation(s)
- Pattamaporn Kwankaew
- Medical Technology, School of Allied Health Sciences, Walailak University, Tha Sala, Nakhon Si Thammarat, Thailand
| | - Aongart Mahittikorn
- Department of Protozoology, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand
| | - Wanida Mala
- Medical Technology Program, Faculty of Science, Nakhon Phanom University, Nakhon Phanom, Thailand
| | | | - Nsoh Godwin Anabire
- Department of Biochemistry & Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Ghana
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), Department of Biochemistry, Cell & Molecular Biology, University of Ghana, Accra, Ghana
| | - Polrat Wilairatana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Manas Kotepui
- Medical Technology Program, Faculty of Science, Nakhon Phanom University, Nakhon Phanom, Thailand.
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Wu Q, Rafatian N, Wagner KT, Blamer J, Smith J, Okhovatian S, Aggarwal P, Wang EY, Banerjee A, Zhao Y, Nash TR, Lu RXZ, Portillo-Esquivel LE, Li CY, Kuzmanov U, Mandla S, Virlee E, Landau S, Lai BF, Gramolini AO, Liu C, Fleischer S, Veres T, Vunjak-Novakovic G, Zhang B, Mossman K, Broeckel U, Radisic M. SARS-CoV-2 pathogenesis in an angiotensin II-induced heart-on-a-chip disease model and extracellular vesicle screening. Proc Natl Acad Sci U S A 2024; 121:e2403581121. [PMID: 38968108 PMCID: PMC11253010 DOI: 10.1073/pnas.2403581121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/20/2024] [Accepted: 05/17/2024] [Indexed: 07/07/2024] Open
Abstract
Adverse cardiac outcomes in COVID-19 patients, particularly those with preexisting cardiac disease, motivate the development of human cell-based organ-on-a-chip models to recapitulate cardiac injury and dysfunction and for screening of cardioprotective therapeutics. Here, we developed a heart-on-a-chip model to study the pathogenesis of SARS-CoV-2 in healthy myocardium established from human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and a cardiac dysfunction model, mimicking aspects of preexisting hypertensive disease induced by angiotensin II (Ang II). We recapitulated cytopathic features of SARS-CoV-2-induced cardiac damage, including progressively impaired contractile function and calcium handling, apoptosis, and sarcomere disarray. SARS-CoV-2 presence in Ang II-treated hearts-on-a-chip decreased contractile force with earlier onset of contractile dysfunction and profoundly enhanced inflammatory cytokines compared to SARS-CoV-2 alone. Toward the development of potential therapeutics, we evaluated the cardioprotective effects of extracellular vesicles (EVs) from human iPSC which alleviated the impairment of contractile force, decreased apoptosis, reduced the disruption of sarcomeric proteins, and enhanced beta-oxidation gene expression. Viral load was not affected by either Ang II or EV treatment. We identified MicroRNAs miR-20a-5p and miR-19a-3p as potential mediators of cardioprotective effects of these EVs.
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Affiliation(s)
- Qinghua Wu
- Institute of Biomedical Engineering, University of Toronto, Toronto, ONM5S 3G9, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ONM5G 2C4, Canada
| | - Naimeh Rafatian
- Institute of Biomedical Engineering, University of Toronto, Toronto, ONM5S 3G9, Canada
| | - Karl T. Wagner
- Institute of Biomedical Engineering, University of Toronto, Toronto, ONM5S 3G9, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ONM5S 3E5, Canada
| | - Jacob Blamer
- Department of Pediatrics, Section of Genomic Pediatrics, Medical College of Wisconsin, Milwaukee, WI53226
| | - Jacob Smith
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ONM5S 3E5, Canada
| | - Sargol Okhovatian
- Institute of Biomedical Engineering, University of Toronto, Toronto, ONM5S 3G9, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ONM5G 2C4, Canada
| | - Praful Aggarwal
- Department of Pediatrics, Section of Genomic Pediatrics, Medical College of Wisconsin, Milwaukee, WI53226
| | - Erika Yan Wang
- Institute of Biomedical Engineering, University of Toronto, Toronto, ONM5S 3G9, Canada
| | - Arinjay Banerjee
- Department of Medicine, McMaster University, Toronto, ONL8S 4L8, Canada
- Vaccine and Infectious Disease Organization, Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SKS7N 5E3, Canada
| | - Yimu Zhao
- Department of Biomedical Engineering, Columbia University, New York, NY10027
| | - Trevor R. Nash
- Department of Biomedical Engineering, Columbia University, New York, NY10027
| | - Rick Xing Ze Lu
- Institute of Biomedical Engineering, University of Toronto, Toronto, ONM5S 3G9, Canada
| | | | - Chen Yu Li
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ONM5S 3E5, Canada
| | - Uros Kuzmanov
- Department of Physiology, University of Toronto, Toronto, ONM5S 1A8, Canada
- Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ONM5G 1M1, Canada
| | - Serena Mandla
- Toronto General Hospital Research Institute, University Health Network, Toronto, ONM5G 2C4, Canada
| | - Elizabeth Virlee
- Department of Pediatrics, Section of Genomic Pediatrics, Medical College of Wisconsin, Milwaukee, WI53226
| | - Shira Landau
- Institute of Biomedical Engineering, University of Toronto, Toronto, ONM5S 3G9, Canada
| | - Benjamin Fook Lai
- Institute of Biomedical Engineering, University of Toronto, Toronto, ONM5S 3G9, Canada
| | - Anthony O. Gramolini
- Department of Physiology, University of Toronto, Toronto, ONM5S 1A8, Canada
- Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ONM5G 1M1, Canada
| | - Chuan Liu
- Institute of Biomedical Engineering, University of Toronto, Toronto, ONM5S 3G9, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ONM5G 2C4, Canada
- Terrence Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, ONM5S 3E1, Canada
| | - Sharon Fleischer
- Department of Biomedical Engineering, Columbia University, New York, NY10027
| | - Teodor Veres
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ONM5S 3G8, Canada
- Medical Devices Research Center, Life Sciences Division, National Research Council Canada, Montreal, QCH4P 2R2, Canada
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering, Columbia University, New York, NY10027
- Department of Medicine, Columbia University, New York, NY10032
| | - Boyang Zhang
- Department of Chemical Engineering, McMaster University, Hamilton, ONL8S 4L8, Canada
| | - Karen Mossman
- Department of Medicine, McMaster University, Toronto, ONL8S 4L8, Canada
| | - Ulrich Broeckel
- Department of Pediatrics, Section of Genomic Pediatrics, Medical College of Wisconsin, Milwaukee, WI53226
| | - Milica Radisic
- Institute of Biomedical Engineering, University of Toronto, Toronto, ONM5S 3G9, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ONM5G 2C4, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ONM5S 3E5, Canada
- Terrence Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, ONM5S 3E1, Canada
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Takahashi K, Okazawa T, Shingaki T, Furuya K, Kimura J, Ohmori K. Tumour necrosis factor-α induces C-C motif chemokine ligand 5 production in canine keratinocytes. Vet Dermatol 2024; 35:219-225. [PMID: 38111073 DOI: 10.1111/vde.13227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/06/2023] [Revised: 10/17/2023] [Accepted: 12/03/2023] [Indexed: 12/20/2023]
Abstract
BACKGROUND C-C motif chemokine ligand (CCL)5 induces skin inflammation in healthy dogs. In addition, CCL5 is overexpressed in the skin of experimental models of canine atopic dermatitis (cAD). Tumour necrosis factor (TNF)-α has been shown to be upregulated in cAD. However, it remains unclear whether TNF-α induces CCL5 production in canine keratinocytes. HYPOTHESIS/OBJECTIVES To determine the effect of TNF-α on CCL5 production in canine keratinocyte culture and investigate possible synergy with interferon (IFN)-γ and interleukin (IL)-4. MATERIALS AND METHODS CCL5 protein concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the culture supernatant of a cell line of canine progenitor epidermal keratinocyte (CPEK) cells stimulated with TNF-α with or without inhibitors of the TNF receptor signalling pathway. CCL5 protein concentrations also were measured in CPEK cells stimulated with TNF-α in the absence or presence of IFN-γ, a T-helper (Th)1-type cytokine, and/or IL-4, a Th2-type cytokine. RESULTS TNF-α increased CCL5 production in CPEK cells in time- and dose-dependent manners. Inhibitors of the TNF receptor signalling pathway diminished CCL5 production. Although neither IFN-γ nor IL-4 alone induced CCL5 production in CPEK cells, the combination of TNF-α and IFN-γ, and not IL-4, synergistically enhanced CCL5 production in these cells. CONCLUSIONS AND CLINICAL RELEVANCE TNF-α may be involved in skin inflammation in dogs by promoting CCL5 production in keratinocytes. Furthermore, the synergistic effect of TNF-α and IFN-γ suggests that the local Th1-type milieu may aggravate skin inflammation. Further studies are required to elucidate the role of TNF-α-induced CCL5 production of keratinocytes in the pathogenesis of cAD.
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Affiliation(s)
- Kaho Takahashi
- Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
| | - Taiga Okazawa
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
| | - Tomoaki Shingaki
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
| | - Keiko Furuya
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
| | - Junpei Kimura
- College of Veterinary Medicine and Research Institute for Veterinary Medicine, Seoul National University, Seoul, Korea
| | - Keitaro Ohmori
- Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
- Division of Animal Life Science, Institute of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
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6
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Zhou S, Liu C, Wang J, Ye J, Lian Q, Gan L, Deng S, Xu T, Guo Y, Li W, Zhang Z, Yang GY, Tang Y. CCL5 mediated astrocyte-T cell interaction disrupts blood-brain barrier in mice after hemorrhagic stroke. J Cereb Blood Flow Metab 2024; 44:367-383. [PMID: 37974301 PMCID: PMC10870968 DOI: 10.1177/0271678x231214838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/08/2023] [Revised: 10/17/2023] [Accepted: 10/24/2023] [Indexed: 11/19/2023]
Abstract
The crosstalk between reactive astrocytes and infiltrated immune cells plays a critical role in maintaining blood-brain barrier (BBB) integrity. However, how astrocytes interact with immune cells and the effect of their interaction on BBB integrity after hemorrhagic stroke are still unclear. By performing RNA sequencing in astrocytes that were activated by interleukin-1α (IL-1α), tumor necrosis factor α (TNFα), and complement component 1q (C1q) treatment, we found CCL5 was among the top upregulated genes. Immunostaining and western blot results demonstrated that CCL5 was increased in mice brain after hemorrhagic stroke. Flow cytometry showed that knockout of astrocytic CCL5 reduced the infiltration of CD8+ but not CD4+ T and myeloid cells into the brain (p < 0.05). In addition, knockout CCL5 in astrocytes increased tight junction-related proteins ZO-1 and Occludin expression; reduced Evans blue leakage, perforin and granzyme B expression; improved neurobehavioral outcomes in hemorrhagic stroke mice (p < 0.05), while transplantation of CD8+ T cells reversed these protective effects. Moreover, co-culture of CD8+ T cells with bEnd.3 cells induced the apoptosis of bEnd.3 cells, which was rescued by inhibiting perforin. In conclusion, our study suggests that CCL5 mediated crosstalk between astrocytes and CD8+ T cells represents an important therapeutic target for protecting BBB in stroke.
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Affiliation(s)
- Shiyi Zhou
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Chang Liu
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Jixian Wang
- Department of Rehabilitation Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing Ye
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Qianyuan Lian
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Lin Gan
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Shiyu Deng
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Tongtong Xu
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yiyan Guo
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Wanlu Li
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Zhijun Zhang
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Guo-Yuan Yang
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yaohui Tang
- Shanghai Sixth People’s Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
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Shao L, Fu J, Xie L, Cai G, Cheng Y, Zheng N, Zeng P, Yan X, Ling Z, Ye S. Fecal Microbiota Underlying the Coexistence of Schizophrenia and Multiple Sclerosis in Chinese Patients. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2023; 2023:5602401. [PMID: 37680457 PMCID: PMC10482522 DOI: 10.1155/2023/5602401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 05/05/2023] [Revised: 07/11/2023] [Accepted: 08/24/2023] [Indexed: 09/09/2023]
Abstract
Both schizophrenia (SZ) and multiple sclerosis (MS) affect millions of people worldwide and impose a great burden on society. Recent studies indicated that MS elevated the risk of SZ and vice versa, whereas the underlying pathological mechanisms are still obscure. Considering that fecal microbiota played a vital role in regulating brain functions, the fecal microbiota and serum cytokines from 90 SZ patients and 71 age-, gender-, and BMI-matched cognitively normal subjects (referred as SZC), 22 MS patients and 33 age-, gender-, and BMI-matched healthy subjects (referred as MSC) were analyzed. We found that both diseases demonstrated similar microbial diversity and shared three differential genera, including the down-regulated Faecalibacterium, Roseburia, and the up-regulated Streptococcus. Functional analysis indicated that the three genera were involved in pathways such as "carbohydrate metabolism" and "amino acid metabolism." Moreover, the variation patterns of serum cytokines associated with MS and SZ patients were a bit different. Among the six cytokines perturbed in both diseases, TNF-α increased, while IL-8 and MIP-1α decreased in both diseases. IL-1ra, PDGF-bb, and RANTES were downregulated in MS patients but upregulated in SZ patients. Association analyses showed that Faecalibacterium demonstrated extensive correlations with cytokines in both diseases. Most notably, Faecalibacterium correlated negatively with TNF-α. In other words, fecal microbiota such as Faecalibacterium may contribute to the coexistence of MS and SZ by regulating serum cytokines. Our study revealed the potential roles of fecal microbiota in linking MS and SZ, which paves the way for developing gut microbiota-targeted therapies that can manage two diseases with a single treat.
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Affiliation(s)
- Li Shao
- School of Clinical Medicine, Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Jinlong Fu
- School of Clinical Medicine, Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Lulu Xie
- Rugao Experimental Primary School, Nantong, China
| | - Guangyong Cai
- Department of Rehabilitation Medicine, Lishui Second People's Hospital, Lishui, China
| | - Yiwen Cheng
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
| | - Nengneng Zheng
- Department of Obstetrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ping Zeng
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiumei Yan
- Department of Rehabilitation Medicine, Lishui Second People's Hospital, Lishui, China
| | - Zongxin Ling
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
| | - Shiwei Ye
- Department of Psychiatry, Lishui Second People's Hospital, Lishui, China
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8
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Differential mRNA and miRNA Profiles Reveal the Potential Roles of Genes and miRNAs Involved in LPS Infection in Chicken Macrophages. Genes (Basel) 2021; 12:genes12050760. [PMID: 34067819 PMCID: PMC8155903 DOI: 10.3390/genes12050760] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/18/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 12/12/2022] Open
Abstract
Lipopolysaccharide (LPS) is a component of the cell wall of Gram-negative bacteria, and triggers an inflammatory response both in vitro and in vivo. Here, we used LPS from Escherichia coli serotype enteritidis to stimulate chicken macrophages (HD11) and conducted the transcriptome analysis using a bioinformatics approach to explore the functions of immune-related genes and miRNAs. In total, 1759 differentially expressed genes (DEGs) and 18 differentially expressed (DE)-miRNAs were detected during LPS infection. At 6 h post infection, 1025 DEGs and 10 miRNAs were up-regulated, and 734 DEGs and 8 DE-miRNAs were down-regulated. Based on both RNA hybrid and miRanda systems, 55 DEGs could be targeted by 14 DE-miRNAs. The target genes were related to the immune response, such as IRF8, STAT3, TRAF7, and other potential candidate genes. The DE-miRNAs miR146a-3p, miR6583-5p, and miR30c-2-3p were investigated further. They were predicted to target 34 genes that may also be candidates for immune-related miRNAs and genes. Our results enhanced our understanding of the pathogenic mechanisms of Gram-negative bacteria in chickens.
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Lapiere A, Geiger M, Robert V, Demarquay C, Auger S, Chadi S, Benadjaoud M, Fernandes G, Milliat F, Langella P, Benderitter M, Chatel JM, Sémont A. Prophylactic Faecalibacterium prausnitzii treatment prevents the acute breakdown of colonic epithelial barrier in a preclinical model of pelvic radiation disease. Gut Microbes 2020; 12:1-15. [PMID: 32985332 PMCID: PMC7524396 DOI: 10.1080/19490976.2020.1812867] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/03/2023] Open
Abstract
Every year, millions of people around the world benefit from radiation therapy to treat cancers localized in the pelvic area. Damage to healthy tissue in the radiation field can cause undesirable toxic effects leading to gastrointestinal complications called pelvic radiation disease. A change in the composition and/or function of the microbiota could contribute to radiation-induced gastrointestinal toxicity. In this study, we tested the prophylactic effect of a new generation of probiotic like Faecalibacterium prausnitzii (F. prausnitzii) on acute radiation-induced colonic lesions. Experiments were carried out in a preclinical model of pelvic radiation disease. Rats were locally irradiated at 29 Gray in the colon resulting in colonic epithelial barrier rupture. Three days before the irradiation and up to 3 d after the irradiation, the F. prausnitzii A2-165 strain was administered daily (intragastrically) to test its putative protective effects. Results showed that prophylactic F. prausnitzii treatment limits radiation-induced para-cellular hyperpermeability, as well as the infiltration of neutrophils (MPO+ cells) in the colonic mucosa. Moreover, F. prausnitzii treatment reduced the severity of the morphological change of crypts, but also preserved the pool of Sox-9+ stem/progenitor cells, the proliferating epithelial PCNA+ crypt cells and the Dclk1+/IL-25+ differentiated epithelial tuft cells. The benefit of F. prausnitzii was associated with increased production of IL-18 by colonic crypt epithelial cells. Thus, F. prausnitzii treatment protected the epithelial colonic barrier from colorectal irradiation. New-generation probiotics may be promising prophylactic treatments to reduce acute side effects in patients treated with radiation therapy and may improve their quality of life.
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Affiliation(s)
- Alexia Lapiere
- Department of RAdiobiology and Regenerative MEDicine (SERAMED), Laboratory of MEDical Radiobiology (Lrmed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France
| | - Mallia Geiger
- Department of RAdiobiology and Regenerative MEDicine (SERAMED), Laboratory of MEDical Radiobiology (Lrmed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France
| | - Véronique Robert
- INRAE, AgroParisTech, Micalis Institute, Paris-Saclay University, Jouy-en-Josas, France
| | - Christelle Demarquay
- Department of RAdiobiology and Regenerative MEDicine (SERAMED), Laboratory of MEDical Radiobiology (Lrmed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France
| | - Sandrine Auger
- INRAE, AgroParisTech, Micalis Institute, Paris-Saclay University, Jouy-en-Josas, France
| | - Sead Chadi
- INRAE, AgroParisTech, Micalis Institute, Paris-Saclay University, Jouy-en-Josas, France
| | - Mohamedamine Benadjaoud
- Department of RAdiobiology and Regenerative MEDicine (SERAMED), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France
| | - Gabriel Fernandes
- René Rachou Institute, Oswaldo Cruz Foundation, Belo Horizonte, MG, Brazil
| | - Fabien Milliat
- Department of RAdiobiology and Regenerative MEDicine (SERAMED), Laboratory of MEDical Radiobiology (Lrmed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France
| | - Philippe Langella
- INRAE, AgroParisTech, Micalis Institute, Paris-Saclay University, Jouy-en-Josas, France
| | - Marc Benderitter
- Department of RAdiobiology and Regenerative MEDicine (SERAMED), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France
| | - Jean-Marc Chatel
- INRAE, AgroParisTech, Micalis Institute, Paris-Saclay University, Jouy-en-Josas, France
| | - Alexandra Sémont
- Department of RAdiobiology and Regenerative MEDicine (SERAMED), Laboratory of MEDical Radiobiology (Lrmed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France,CONTACT : Alexandra Sémont, Department of RAdiobiology and Regenerative MEDicine (SERAMED), Laboratory of MEDical Radiobiology (Lrmed), Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses92260, France
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Abstract
Chemokines are a family of small cytokines that share a typical key structure that is stabilized by disulfide bonds between the cysteine residues at the NH2-terminal of the protein, and they are secreted by a great variety of cells in several different conditions. Their function is directly dependent on their interactions with their receptors. Chemokines are involved in cell maturation and differentiation, infection, autoimmunity, cancer, and, in general, in any situation where immune components are involved. However, their role in postfracture inflammation and fracture healing is not yet well established. In this article, we will discuss the response of chemokines to bone fracture and their potential roles in postfracture inflammation and healing based on data from our studies and from other previously published studies.
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Affiliation(s)
- Bouchra Edderkaoui
- Musculoskeletal Disease Center, Loma Linda VA Health Care Systems, Loma Linda, CA, USA
- Department of Medicine, Loma Linda University, Loma Linda, CA, USA
- *Correspondence: Bouchra Edderkaoui,
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11
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Vitamin D decreases the secretion of eotaxin and RANTES in nasal polyp fibroblasts derived from Taiwanese patients with chronic rhinosinusitis with nasal polyps. Kaohsiung J Med Sci 2014; 31:63-9. [PMID: 25645983 DOI: 10.1016/j.kjms.2014.11.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/16/2014] [Revised: 10/27/2014] [Accepted: 11/10/2014] [Indexed: 11/24/2022] Open
Abstract
Eosinophils are important inflammatory cells involved in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Vitamin D and its derivatives, in addition to their classic role as regulators of electrolytes homeostasis, have modulatory effects in immunological and inflammatory responses. Such properties suggest that vitamin D might also play a role in inflammatory airway diseases such as CRSwNP. In this study, we investigated the effect of vitamin D derivatives (calcitriol and tacalcitol) on the secretion of eotaxin and Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES), the two major eosinophil chemoattractants, in fibroblasts derived from the polyps of Taiwanese CRSwNP patients. Patients diagnosed with eosinophilic CRSwNP but without malignancies or asthma and undergoing elective endoscopic sinus surgery were recruited. Three primary fibroblast cultures were established using the polyp specimens obtained from these patients. The third to eighth passages of the fibroblasts were used for in vitro studies. Nasal polyp-derived fibroblasts were stimulated with IL-1β (10 ng/mL) for 24 hours, followed by replacement with media alone or with calcitriol or tacalcitol (10 μM) and incubation for another 24 hours. After the treatments, the levels of secreted eotaxin and RANTES were evaluated by ELISA assays. The results showed that IL-1β could substantially stimulate the secretion of eotaxin (p < 0.01) and RANTES (p < 0.01) in nasal polyp-derived fibroblasts. More importantly, this stimulatory effect was significantly suppressed by adding calcitriol (p ≤ 0.002 for eotaxin and p ≤ 0.008 for RANTES) or tacalcitol (p ≤ 0.009 for eotaxin and p ≤ 0.02 for RANTES). Therefore, the inhibitory effect of vitamin D derivatives on eotaxin and RANTES secretion might shed light not only on the disease mechanism, but also on the potential use of vitamin D in pharmacotherapy of Taiwanese patients with CRSwNP.
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Pais R, Zietek T, Hauner H, Daniel H, Skurk T. RANTES (CCL5) reduces glucose-dependent secretion of glucagon-like peptides 1 and 2 and impairs glucose-induced insulin secretion in mice. Am J Physiol Gastrointest Liver Physiol 2014; 307:G330-7. [PMID: 24875103 DOI: 10.1152/ajpgi.00329.2013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 01/31/2023]
Abstract
Type 2 diabetes is associated with elevated circulating levels of the chemokine RANTES and with decreased plasma levels of the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 is a peptide secreted from intestinal L-cells upon nutrient ingestion. It enhances insulin secretion from pancreatic β-cells and protects from β-cell loss but also promotes satiety and weight loss. In search of chemokines that may reduce GLP-1 secretion we identified RANTES and show that it reduces glucose-stimulated GLP-1 secretion in the human enteroendocrine cell line NCI-H716, blocked by the antagonist Met-RANTES, and in vivo in mice. RANTES exposure to mouse intestinal tissues lowers transport function of the intestinal glucose transporter SGLT1, and administration in mice reduces plasma GLP-1 and GLP-2 levels after an oral glucose load and thereby impairs insulin secretion. These data show that RANTES is involved in altered secretion of glucagon-like peptide hormones most probably acting through SGLT1, and our study identifies the RANTES-receptor CCR1 as a potential target in diabetes therapy.
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Affiliation(s)
- Ramona Pais
- ZIEL Research Center of Nutrition and Food Sciences, Nutritional Medicine, Technische Universität München, Freising, Germany; ZIEL Research Center of Nutrition and Food Sciences, Abteilung Biochemie, Technische Universität München, Freising, Germany; and
| | - Tamara Zietek
- ZIEL Research Center of Nutrition and Food Sciences, Abteilung Biochemie, Technische Universität München, Freising, Germany; and
| | - Hans Hauner
- ZIEL Research Center of Nutrition and Food Sciences, Nutritional Medicine, Technische Universität München, Freising, Germany; Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Hannelore Daniel
- ZIEL Research Center of Nutrition and Food Sciences, Abteilung Biochemie, Technische Universität München, Freising, Germany; and
| | - Thomas Skurk
- ZIEL Research Center of Nutrition and Food Sciences, Nutritional Medicine, Technische Universität München, Freising, Germany; Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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Abstract
Background The systemic inflammatory response to Clostridium difficile infection (CDI) is incompletely defined, particularly for patients with severe disease. Methods Analysis of 315 blood samples from 78 inpatients with CDI (cases), 100 inpatients with diarrhea without CDI (inpatient controls), and 137 asymptomatic outpatient controls without CDI was performed. Serum or plasma was obtained from subjects at the time of CDI testing or shortly thereafter. Severe cases had intensive care unit admission, colectomy, or death due to CDI within 30 days after diagnosis. Thirty different circulating inflammatory mediators were quantified using an antibody-linked bead array. Principal component analysis (PCA), multivariate analysis of variance (MANOVA), and logistic regression were used for analysis. Results Based on MANOVA, cases had a significantly different inflammatory profile from outpatient controls but not from inpatient controls. In logistic regression, only chemokine (C-C motif) ligand 5 (CCL5) levels were associated with cases vs. inpatient controls. Several mediators were associated with cases vs. outpatient controls, especially hepatocyte growth factor, CCL5, and epithelial growth factor (inversely associated). Eight cases were severe and associated with elevations in IL-8, IL-6, and eotaxin. Conclusions A broad systemic inflammatory response occurs during CDI and severe cases appear to differ from non-severe infections.
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Pucheu-Haston CM, Kasparek KA, Stout RW, Kearney MT, Hammerberg B. Effects of pentoxifylline on immediate and late-phase cutaneous reactions in response to anti-immunoglobulin E antibodies in clinically normal dogs. Am J Vet Res 2014; 75:152-60. [PMID: 24471751 DOI: 10.2460/ajvr.75.2.152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To characterize the effects of pentoxifylline on the gross and microscopic variables associated with immediate and late-phase inflammation following injection of IgE-specific antibodies in the skin of clinically normal dogs. ANIMALS 6 healthy adult mixed-breed dogs. PROCEDURES Intradermal injections (0.1 mL each) of PBS solution, histamine phosphate, and cross-linking rabbit-origin anti-canine IgE antibodies (3 injections/dog) were administered at 0 hours on day 0; wheal sizes were evaluated at 20 minutes, 6 hours, and 24 hours. Biopsy specimens of injected and noninjected skin were collected 24 hours after injection. On day 2, treatment with pentoxifylline (20 mg/kg, PO, q 8 h) was initiated and continued until day 30. For each dog, injection, measurement, and biopsy procedures were repeated on days 30 to 31 and on days 37 to 38 (ie, after discontinuation of pentoxifylline administration). RESULTS Pentoxifylline administration was associated with a significant decrease in wheal size at 6 and 24 hours (but not at 20 minutes) after injection of anti-canine IgE. Repeated injections performed 1 week after drug discontinuation revealed partial recovery of the 6-hour cutaneous reaction and complete recovery of the 24-hour cutaneous reaction. Pentoxifylline administration was also associated with inhibition of mast cell degranulation and significant decreases in the total numbers of cutaneous inflammatory cells and eosinophils, compared with pretreatment findings. CONCLUSIONS AND CLINICAL RELEVANCE In clinically normal dogs, pentoxifylline effectively impaired late-phase reactions but not immediate reactions at sites of intradermal injection of IgE-specific antibodies by inhibiting mast cell degranulation and recruitment of cutaneous inflammatory cells, especially eosinophils.
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Affiliation(s)
- Cherie M Pucheu-Haston
- Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803
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15
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Di Penta A, Chiba A, Alloza I, Wyssenbach A, Yamamura T, Villoslada P, Miyake S, Vandenbroeck K. A trifluoromethyl analogue of celecoxib exerts beneficial effects in neuroinflammation. PLoS One 2013; 8:e83119. [PMID: 24349442 PMCID: PMC3859644 DOI: 10.1371/journal.pone.0083119] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/14/2013] [Accepted: 10/31/2013] [Indexed: 12/31/2022] Open
Abstract
Celecoxib is a selective cyclooxygenase-2 (COX2) inhibitor. We have previously shown that celecoxib inhibits experimental autoimmune encephalomyelitis (EAE) in COX-2-deficient mice, suggestive for a mode of action involving COX2-independent pathways. In the present study, we tested the effect of a trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2 inhibitory activity in two models of neuroinflammation, i.e. cerebellar organotypic cultures challenged with LPS and the EAE mouse model for multiple sclerosis. TFM-C inhibited secretion of IL-1β, IL-12 and IL-17, enhanced that of TNF-α and RANTES, reduced neuronal axonal damage and protected from oxidative stress in the organotypic model. TFM-C blocked TNF-α release in microglial cells through a process involving intracellular retention, but induced TNF-α secretion in primary astrocyte cultures. Finally, we demonstrate that TFM-C and celecoxib ameliorated EAE with equal potency. This coincided with reduced secretion of IL-17 and IFN-γ by MOG-reactive T-cells and of IL-23 and inflammatory cytokines by bone marrow-derived dendritic cells. Our study reveals that non-coxib analogues of celecoxib may have translational value in the treatment of neuro-inflammatory conditions.
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Affiliation(s)
- Alessandra Di Penta
- Neurogenomiks Laboratory, University of Basque Country (UPV/ EHU), Zamudio, Spain
- Achucarro Basque Center for Neuroscience, Zamudio, Spain
| | - Asako Chiba
- Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
- Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
| | - Iraide Alloza
- Neurogenomiks Laboratory, University of Basque Country (UPV/ EHU), Zamudio, Spain
- Achucarro Basque Center for Neuroscience, Zamudio, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Ane Wyssenbach
- Neurotek Laboratory, University of Basque Country (UPV/EHU), Zamudio, Spain
| | - Takashi Yamamura
- Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Pablo Villoslada
- Center of Neuroimmunology, Institute of Biomedical Research August Pi Sunyer (IDIBAPS) – Hospital Clinic of Barcelona, Barcelona, Spain
| | - Sachiko Miyake
- Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
- Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
| | - Koen Vandenbroeck
- Neurogenomiks Laboratory, University of Basque Country (UPV/ EHU), Zamudio, Spain
- Achucarro Basque Center for Neuroscience, Zamudio, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- * E-mail:
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Magkrioti C, Aidinis V. Autotaxin and lysophosphatidic acid signalling in lung pathophysiology. World J Respirol 2013; 3:77-103. [DOI: 10.5320/wjr.v3.i3.77] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/29/2013] [Revised: 10/03/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
Autotaxin (ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid (LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors (LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysiological situations in vivo and in human diseases.
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Chemokines: structure, receptors and functions. A new target for inflammation and asthma therapy? Mediators Inflamm 2012; 5:393-416. [PMID: 18475745 PMCID: PMC2365823 DOI: 10.1155/s0962935196000567] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/18/2022] Open
Abstract
Five to 10% of the human population have a disorder of the respiratory tract called 'asthma'. It has been known as a potentially dangerous disease for over 2000 years, as it was already described by Hippocrates and recognized as a disease entity by Egyptian and Hebrew physicians. At the beginning of this decade, there has been a fundamental change in asthma management. The emphasis has shifted from symptom relief with bronchodilator therapies (e.g. beta(2)-agonists) to a much earlier introduction of anti-inflammatory treatment (e.g. corticosteroids). Asthma is now recognized to be a chronic inflammatory disease of the airways, involving various inflammatory cells and their mediators. Although asthma has been the subject of many investigations, the exact role of the different inflammatory cells has not been elucidated completely. Many suggestions have been made and several cells have been implicated in the pathogenesis of asthma, such as the eosinophils, the mast cells, the basophils and the lymphocytes. To date, however, the relative importance of these cells is not completely understood. The cell type predominantly found in the asthmatic lung is the eosinophil and the recruitment of these eosinophils can be seen as a characteristic of asthma. In recent years much attention is given to the role of the newly identified chemokines in asthma pathology. Chemokines are structurally and functionally related 8-10 kDa peptides that are the products of distinct genes clustered on human chromosomes 4 and 17 and can be found at sites of inflammation. They form a superfamily of proinflammatory mediators that promote the recruitment of various kinds of leukocytes and lymphocytes. The chemokine superfamily can be divided into three subgroups based on overall sequence homology. Although the chemokines have highly conserved amino acid sequences, each of the chemokines binds to and induces the chemotaxis of particular classes of white blood cells. Certain chemokines stimulate the recruitment of multiple cell types including monocytes, lymphocytes, basophils, and eosinophils, which are important cells in asthma. Intervention in this process, by the development of chemokine antagonists, might be the key to new therapy. In this review we present an overview of recent developments in the field of chemokines and their role in inflammations as reported in literature.
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Liu YS, Tsai PW, Wang Y, Fan TC, Hsieh CH, Chang MDT, Pai TW, Huang CF, Lan CY, Chang HT. Chemoattraction of macrophages by secretory molecules derived from cells expressing the signal peptide of eosinophil cationic protein. BMC SYSTEMS BIOLOGY 2012; 6:105. [PMID: 22906315 PMCID: PMC3478170 DOI: 10.1186/1752-0509-6-105] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 03/27/2012] [Accepted: 08/14/2012] [Indexed: 12/12/2022]
Abstract
Background Eosinophil cationic protein is a clinical asthma biomarker that would be released into blood, especially gathered in bronchia. The signal peptide of eosinophil cationic protein (ECPsp) plays an important role in translocating ECP to the extracellular space. We previously reported that ECPsp inhibits microbial growth and regulates the expression of mammalian genes encoding tumor growth factor-α (TGF-α) and epidermal growth factor receptor (EGFR). Results In the present study, we first generated a DNA microarray dataset, which showed that ECPsp upregulated proinflammatory molecules, including chemokines, interferon-induced molecules, and Toll-like receptors. The levels of mRNAs encoding CCL5, CXCL10, CXCL11, CXCL16, STAT1, and STAT2 were increased in the presence of ECPsp by 2.07-, 4.21-, 7.52-, 2.6-, 3.58-, and 1.67-fold, respectively. We then constructed a functional linkage network by integrating the microarray dataset with the pathway database of Kyoto Encyclopedia of Genes and Genomes (KEGG). Follow-up analysis revealed that STAT1 and STAT2, important transcriptional factors that regulate cytokine expression and release, served as hubs to connect the pathways of cytokine stimulation (TGF-α and EGFR pathways) and inflammatory responses. Furthermore, integrating TGF-α and EGFR with the functional linkage network indicated that STAT1 and STAT2 served as hubs that connect two functional clusters, including (1) cell proliferation and survival, and (2) inflammation. Finally, we found that conditioned medium in which cells that express ECPsp had been cultured could chemoattract macrophages. Experimentally, we also demonstrated that the migration of macrophage could be inhibited by the individual treatment of siRNAs of STAT1 or STAT2. Therefore, we hypothesize that ECPsp may function as a regulator for enhancing the migration of macrophages through the upregualtion of the transcriptional factors STAT1 and STAT2. Conclusion The increased expression and release of various cytokines triggered by ECPsp may attract macrophages to bronchia to purge damaged cells. Our approach, involving experimental and computational systems biology, predicts pathways and potential biological functions for further characterization of this novel function of ECPsp under inflammatory conditions.
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Affiliation(s)
- Yu-Shu Liu
- College of Medicine, China Medical University, Taichung, Taiwan
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Mortier A, Gouwy M, Van Damme J, Proost P. Effect of posttranslational processing on the in vitro and in vivo activity of chemokines. Exp Cell Res 2010; 317:642-54. [PMID: 21146523 DOI: 10.1016/j.yexcr.2010.11.016] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/15/2010] [Revised: 11/25/2010] [Accepted: 11/29/2010] [Indexed: 10/18/2022]
Abstract
The CXC and CC chemokine gene clusters provide an abundant number of chemotactic factors selectively binding to shared G protein-coupled receptors (GPCR). Hence, chemokines function in a complex network to mediate migration of the various leukocyte subsets, expressing specific GPCRs during the immune response. Further fine-tuning of the chemokine system is reached through specific posttranslational modifications of the mature proteins. Indeed, enzymatic processing of chemokines during an early phase of inflammation leads to activation of precursor molecules or cleavage into even more active or receptor specific chemokine isoforms. At a further stage, proteolytic processing leads to loss of GPCR signaling, thereby providing natural chemokine receptor antagonists. Finally, further NH(2)-terminal cleavage results in complete inactivation to dampen the inflammatory response. During inflammatory responses, the two chemokines which exist in a membrane-bound form may be released by proteases from the cellular surface. In addition to proteolytic processing, citrullination and glycosylation of chemokines is also important for their biological activity. In particular, citrullination of arginine residues seems to reduce the inflammatory activity of chemokines in vivo. This goes along with other positive and negative regulatory mechanisms for leukocyte migration, such as chemokine synergy and scavenging by decoy receptors.
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Affiliation(s)
- Anneleen Mortier
- Laboratory of Molecular Immunology, Rega Institute, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
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Matsuzaki S, Ishizuka T, Hisada T, Aoki H, Komachi M, Ichimonji I, Utsugi M, Ono A, Koga Y, Dobashi K, Kurose H, Tomura H, Mori M, Okajima F. Lysophosphatidic acid inhibits CC chemokine ligand 5/RANTES production by blocking IRF-1-mediated gene transcription in human bronchial epithelial cells. THE JOURNAL OF IMMUNOLOGY 2010; 185:4863-72. [PMID: 20861350 DOI: 10.4049/jimmunol.1000904] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/23/2022]
Abstract
Lysophosphatidic acid (LPA) is a phospholipid mediator that exerts a variety of biological responses through specific G-protein-coupled receptors (LPA(1)-LPA(5) and P2Y5). LPA is thought to be involved in airway inflammation by regulating the expression of anti-inflammatory and proinflammatory genes. Chemokines such as CCL5/RANTES are secreted from airway epithelium and play a key role in allergic airway inflammation. CCL5/RANTES is a chemoattractant for eosinophils, T lymphocytes, and monocytes and seems to exacerbate asthma. We stimulated CCL5/RANTES production in a human bronchial epithelial cell line, BEAS-2B, with IFN-γ and TNF-α. When LPA was added, CCL5/RANTES mRNA expression and protein secretion were inhibited, despite the presence of IFN-γ and TNF-α. The LPA effect was attenuated by Ki16425, a LPA(1)/LPA(3) antagonist, but not by dioctylglycerol pyrophosphate 8:0, an LPA(3) antagonist. Pertussis toxin, the inhibitors for PI3K and Akt also attenuated the inhibitory effect of LPA on CCL5/RANTES secretion. We also identify the transcription factor IFN regulatory factor-1 (IRF-1) as being essential for CCL5/RANTES production. Interestingly, LPA inhibited IFN-γ and TNF-α-induced IRF-1 activation by blocking the binding of IRF-1 to its DNA consensus sequence without changing IRF-1 induction and its nuclear translocation. Ki16425, pertussis toxin, and PI3K inhibitors attenuated the inhibitory effect of LPA on IRF-1 activation. Our results suggest that LPA inhibits IFN-γ- and TNF-α-induced CCL5/RANTES production in BEAS-2B cells by blocking the binding of IRF-1 to the CCL5/RANTES promoter. LPA(1) coupled to G(i) and activation of PI3K is required for this unique effect.
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Affiliation(s)
- Shinichi Matsuzaki
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
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Schøller J, Singh M, Bergmeier L, Brunstedt K, Wang Y, Whittall T, Rahman D, Pido-Lopez J, Lehner T. A recombinant human HLA-class I antigen linked to dextran elicits innate and adaptive immune responses. J Immunol Methods 2010; 360:1-9. [DOI: 10.1016/j.jim.2010.05.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/23/2010] [Revised: 05/18/2010] [Accepted: 05/25/2010] [Indexed: 10/19/2022]
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23
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Immunologic messenger molecules: cytokines, interferons, and chemokines. J Allergy Clin Immunol 2009; 125:S53-72. [PMID: 19932918 DOI: 10.1016/j.jaci.2009.07.008] [Citation(s) in RCA: 282] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/15/2009] [Revised: 07/09/2009] [Accepted: 07/10/2009] [Indexed: 02/07/2023]
Abstract
Cytokines and chemokines are secreted proteins involved in numerous aspects of cell growth, differentiation, and activation. A prominent feature of these molecules is their effect on the immune system with regard to cell trafficking and development of immune tissue and organs. The nature of an immune response determines which cytokines are produced and ultimately whether the response is cytotoxic, humoral, cell mediated, or allergic. For this chapter, cytokines are grouped according to those that are predominantly antigen-presenting cell or T lymphocyte derived; that mediate cytotoxic, humoral, cell mediated, and allergic immunity; or that are immunosuppressive. A discussion of chemokine function and their role in cell trafficking and disease follows.
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Tian M, Liu F, Wen GY, Shi SY, Chen RH, Zhao DY. Effect of variation in RANTES promoter on serum RANTES levels and risk of recurrent wheezing after RSV bronchiolitis in children from Han, Southern China. Eur J Pediatr 2009; 168:963-7. [PMID: 19005677 DOI: 10.1007/s00431-008-0870-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 10/10/2008] [Accepted: 10/28/2008] [Indexed: 01/22/2023]
Abstract
To investigate the association among RANTES (regulated on activation normal T cell expressed and secreted) gene promoter polymorphism, serum RANTES levels, and recurrent wheezing after RSV (respiratory syncytial virus) bronchiolitis in children (1-12 months of age) from Han, Southern china. Three hundred twenty children with RSV bronchiolitis and 272 controls were enrolled in the 3-year follow-up study. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP), enzyme-linked immunosorbent assay (ELISA) kit and luciferase analysis were the mainly used methods, which were used to genotype the RANTES (-403 G/A), assess the serum RANTES levels and the RANTES promoter activity. As the results showed, the RANTES (-403 G/A) in the promoter region was associated with recurrent wheezing after RSV bronchiolitis (p < 0.05) and serum RANTES levels (RANTES genotype G/G: 26.03 +/- 7.46 ng/ml G/A: 28.22 +/- 6.44 ng/ml A/A: 30.12 +/- 5.88 ng/ml). Functional analyses of RANTES promoter activity indicated that the RANTES (-403 G to A) mutation increases the transcriptional activity of the RANTES promoter. In conclusion, the RANTES (-403 G/A) polymorphism increases RANTES transcriptional activity resulted in a high serum RANTES levels, thus increased the risk of recurrent wheezing after RSV bronchiolitis.
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Affiliation(s)
- Man Tian
- Department of Respiratory Medicine, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China
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25
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Kang ZH, Li MB, Wang CY, Dong GL, Zhang HW, Yang JJ, Zheng JY, Li JP, Wang WZ. Generation of rat monoclonal antibodies against human RANTES. Hybridoma (Larchmt) 2008; 27:175-9. [PMID: 18582210 DOI: 10.1089/hyb.2007.0562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/12/2022]
Abstract
RANTES (or regulated upon activation, normal T cell expressed and secreted) belongs to the rapidly growing chemokine family. It is mainly produced by T cells, epithelial cells, monocytes, fibroblasts, and mesanglial cells. Increased RANTES expression has been associated with a wide range of inflammatory disorders and pathologies. Mouse RANTES is the homolog molecule of human RANTES. The two have considerable homology in both sequence and structure. Using hRANTES as immunogen and the technique of rat B lymphocyte hybridoma, we raised two hybridoma cell lines secreting monoclonal antibodies (MAbs) to hRANTES, designated no. 1 and no. 2. Both MAbs can bind the hRANTES in FCM, Western blot analysis, and immunocytochemistry. No. 1 also worked well in immunohistochemistry of rat transplanted intestine, which may recognize the same epitope on human RANTES and rat RANTES. Thus, successful production of rat anti-human RANTES MAbs may provide a useful tool in further exploration of the biological function and pathological significance of RANTES and may provide a new method to judge early rejection after small bowel transplantation.
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Affiliation(s)
- Zhen-Hua Kang
- Department of Gastrointestinal Surgery, Xi Jing Hospital, Fourth Military Medical University, Xi'an, China
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LITCHFIELD T, SMITH C, ATKINSON B, NORRIS P, ELLIOTT P, HASKARD D, LEE T. Eosinophil infiltration into human skin is antigen-dependent in the late-phase reaction. Br J Dermatol 2008. [DOI: 10.1046/j.1365-2133.1996.d01-892.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/20/2022]
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27
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Mobley JL, En Chin J, Richards IM. Section Review Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis: Glucocorticosteroids, old and new: Biological function and use in the treatment of asthma. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.5.7.871] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/05/2022]
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28
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29
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Machado RR, Soares DM, Soares DM, Proudfoot AE, Souza GEP. CCR1 and CCR5 chemokine receptors are involved in fever induced by LPS (E. coli) and RANTES in rats. Brain Res 2007; 1161:21-31. [PMID: 17604006 DOI: 10.1016/j.brainres.2007.05.054] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/08/2006] [Revised: 05/07/2007] [Accepted: 05/08/2007] [Indexed: 01/22/2023]
Abstract
This study, besides examining the involvement of CCR1 and CCR5 receptors in the LPS-induced fever (lipopolysaccharide, Escherichia coli) in male Wistar rats, evaluated if RANTES (regulated on activation, normal T cells expressed and secreted) injected into the preoptic area of the anterior hypothalamus (AH/POA) would promote an integrated febrile response via these receptors. Moreover, the effects of selective and non-selective cyclooxygenase blockers on both fever and the level of prostaglandin (PG)E(2) in the cerebrospinal fluid (CSF) after injection of RANTES into the AH/POA were also investigated. Met-RANTES, CCR1 and CCR5 receptor antagonist, reduced LPS-evoked fever dose dependently. RANTES microinjected into the AH/POA increased the rectal temperature of rats dose dependently and caused a significant decrease in the tail skin temperature and an increase (at 2.5 and 5 h) of the levels of PGE(2) in the CSF. Met-RANTES prevented the fever induced by RANTES. Ibuprofen abolished the fever caused by RANTES between 60 min and 2.5 h, and it reduced the temperature until the end of observation period. Celecoxib blocked the RANTES-induced fever, while indomethacin reduced it in the last 60 min of the experimental period. At 2.5 and 5 h all antipyretics brought the CSF PGE(2) level near to the control. These results indicate that CCR1 and CCR5 receptors are involved in the fever induced by systemic LPS and intrahypothalamic RANTES. RANTES promotes an integrated febrile response accompanied by an increase of CSF PGE(2). The inhibitory effects of celecoxib and ibuprofen suggest that PGE(2) was generated via COX-2. As indomethacin dissociates fever and the decrease of PGE(2) level during the RANTES-induced fever, an alternative COX-2-independent pathway or other mechanisms of action of celecoxib and ibuprofen might be considered.
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Affiliation(s)
- Renes R Machado
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
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30
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Sevigny CP, Li L, Awad AS, Huang L, McDuffie M, Linden J, Lobo PI, Okusa MD. Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition. THE JOURNAL OF IMMUNOLOGY 2007; 178:4240-9. [PMID: 17371980 DOI: 10.4049/jimmunol.178.7.4240] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 11/19/2022]
Abstract
The current studies investigated the in vitro and in vivo effect of adenosine 2A receptor (A(2A)R) agonists to attenuate allogenic immune activation. We performed MLRs with spleen T lymphocytes and APCs isolated from wild-type and A(2A)R knockout mice of both C57BL/6 and BALB/c background strains. Two-way MLR-stimulated T cell proliferation was reduced by ATL313, a selective A(2A)R agonist in a dose-responsive manner (approximately 70%; 10 nM), an effect reversed by the A(2A)R antagonist ZM241385 (100 nM). By one-way MLRs, we observed that ATL313's inhibitory effect was due to effects on both T cells and APCs. ATL313 suppressed the activation markers CD25 and CD40L and the release of inflammatory cytokines IFN-gamma, RANTES, IL-12P(70), and IL-2. ATL313 also increased negative costimulatory molecules programmed death-1 and CTLA-4 expressed on T cells. In lymphocytes activated with anti-CD3e mAb, ATL313 inhibited the phosphorylation of Zap70, an effect that was reversed by the protein kinase A inhibitor H-89. In skin transplants, allograft survival was enhanced with ATL313, an effect blocked by ZM241385. These results indicate that A(2A)R agonists attenuate allogenic recognition by action on both T lymphocytes and APCs in vitro and delayed acute rejection in vivo. We conclude that A(2A)R agonists may represent a new class of compounds for induction therapy in organ transplantation.
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Affiliation(s)
- Charles P Sevigny
- Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
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31
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Liu J, Ma X. Interferon Regulatory Factor 8 Regulates RANTES Gene Transcription in Cooperation with Interferon Regulatory Factor-1, NF-κB, and PU.1. J Biol Chem 2006; 281:19188-95. [PMID: 16707500 DOI: 10.1074/jbc.m602059200] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/06/2022] Open
Abstract
Interferon regulatory factor (IRF)-8 is a member of the IRF family of transcription factors important in interferon-gamma-mediated signaling and in the development and function of dendritic cells. Regulated on activation, normal T cell expressed and secreted (RANTES, or CCL5) is a member of the CC chemokine family of proteins, strongly chemoattractant for several important immune cell types in host defense against infectious agents and cancer. Here we report that RANTES expression in IRF-8-null macrophages stimulated with interferon-gamma and lipopolysaccharide is markedly decreased. IRF-8 can activate RANTES gene transcription in synergism with IRF-1. Interestingly, IRF-8 can activate RANTES transcription independently of IRF-1 through direct physical interactions with NF-kappaB c-Rel and PU.1 via the NF-kappaB element located at -88 to -79 in vitro and in vivo. This study uncovers a novel role of IRF-8 in the regulation of RANTES gene expression and the underlying molecular mechanisms whereby IRF-8 interacts with several other important transcription factors to initiate innate immune responses to pathogenic and inflammatory challenges by activating the RANTES gene.
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Affiliation(s)
- Jianguo Liu
- Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021, USA
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33
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Elsner J, Dulkys Y, Gupta S, Escher SE, Forssmann WG, Kapp A, Forssmann U. Differential pattern of CCR1 internalization in human eosinophils: prolonged internalization by CCL5 in contrast to CCL3. Allergy 2005; 60:1386-93. [PMID: 16197470 DOI: 10.1111/j.1398-9995.2005.00893.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Whereas recent studies underlie the fundamental importance of the CC chemokine receptor 3 (CCR3) for the recruitment of eosinophils in allergic diseases, controversial data exist about the relevance of CCR1 on eosinophils. Therefore, the purpose of this study was to investigate the expression and regulation of CCR1 on eosinophils. METHODS Flow cytometric analysis of whole blood eosinophils and CD16-negative selected eosinophils from healthy nonatopic donors and from patients with atopic disorders was performed and CCR1 receptor internalization and re-expression were studied. RESULTS Flow cytometric analysis of whole blood eosinophils revealed that 17.8% of the donors expressed high levels of CCR1 (CCR1high) and 82.2% low levels of CCR1 (CCR1low). A significant down-regulation of CCR1 was induced by 24 h preincubation of isolated eosinophils from CCR1high donors either with IL-3, CC chemokine ligand 3 (CCL3), CCL5, CCL7, or CCL13. Internalization experiments using eosinophils from CCR1high donors revealed that CCL5 is more effective to induce CCR1 internalization than CCL3. Whereas CCR1 re-expression after stimulation with CCL3 reached prestimulation levels (120 min: 81.3% relative CCR1 surface expression) CCL5 induced a prolonged CCR1 internalization (120 min: 15.7%). CONCLUSIONS This study demonstrates a distinct pattern of CCR1 internalization and re-expression in human eosinophils between CCL3 and CCL5, as CCL5 induces a prolonged CCR1 internalization and the basic value is not reached after 24 h. Since prolonged receptor internalization plays a central role in chemokine-mediated inhibition of receptor function, CCR1 seems to be an attractive target on human eosinophils for chemokine receptor blockade besides CCR3.
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Affiliation(s)
- J Elsner
- Department of Dermatology and Allergology, Hannover Medical School, Hannover, Germany
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Liu J, Guan X, Ma X. Interferon Regulatory Factor 1 Is an Essential and Direct Transcriptional Activator for Interferon γ-induced RANTES/CCl5 Expression in Macrophages. J Biol Chem 2005; 280:24347-55. [PMID: 15860458 DOI: 10.1074/jbc.m500973200] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/11/2023] Open
Abstract
Interferon regulatory factor 1 (IRF-1) is an important transcription factor in interferon gamma (IFNgamma)-mediated signaling in the development and function of NK cells and cytotoxic T lymphocytes. RANTES (regulated on activation normal T cell expressed and secreted; CCL5) is a member of the CC chemokine family of proteins, which is strongly chemoattractant for several important immune cell types in host defense against infectious agents and cancer. However, the role of IFNgamma and IRF-1 in the regulation of RANTES gene expression and their operative mechanisms in macrophages have not been established. We report here that RANTES expression in IRF-1-null mice, primarily in macrophages, in response to carcinogenic stimulation in vivo and in vitro and to IFNgamma but not to lipopolysaccharide in vitro, was markedly decreased. As a result, RANTES-mediated chemoattraction of CCR5(+) target cells was also severely impaired. Adenovirus-mediated gene transduction of IRF-1 in primary macrophages resulted in enhanced RANTES expression. The IFNgamma and IRF1 response element was localized to a TTTTC motif at -147 to -143 of the mouse RANTES promoter, to which endogenous or recombinant IRF-1 can physically bind in vitro and in vivo. This study uncovers a novel IFNgamma-induced pathway in RANTES expression mediated by IRF-1 in macrophages and elucidates an important host defense mechanism against neoplastic transformation.
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MESH Headings
- Adenoviridae/genetics
- Amino Acid Motifs
- Animals
- Base Sequence
- Blotting, Western
- CD4 Antigens/biosynthesis
- Cell Line
- Cell Line, Tumor
- Cell Movement
- Cell Nucleus/metabolism
- Cell Transformation, Neoplastic
- Chemokine CCL5/metabolism
- Chemokines, CC/metabolism
- Chemotaxis
- Chromatin Immunoprecipitation
- DNA, Complementary/metabolism
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/physiology
- Dose-Response Relationship, Drug
- Enzyme-Linked Immunosorbent Assay
- Gene Expression Regulation
- Humans
- Interferon Regulatory Factor-1
- Interferon-gamma/metabolism
- Lipopolysaccharides/chemistry
- Macrophages/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Molecular Sequence Data
- Mutagenesis
- Phosphoproteins/genetics
- Phosphoproteins/physiology
- Plasmids/metabolism
- Promoter Regions, Genetic
- RNA, Messenger/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Ribonucleases/metabolism
- Sequence Homology, Nucleic Acid
- Time Factors
- Transcriptional Activation
- Transfection
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Affiliation(s)
- Jianguo Liu
- Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021, USA
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35
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Im GJ, Hwang CS, Jung HH. Quantitative expression levels of regulated on activation, normal T cell expressed and secreted and eotaxin transcripts in toluene diisocyanate-induced allergic rats. Acta Otolaryngol 2005; 125:370-7. [PMID: 15823807 DOI: 10.1080/00016480510003156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/22/2022]
Abstract
CONCLUSION These results suggest that eotaxin may play a predominant role in controlling antigen-induced eosinophil recruitment into tissue. Objective To investigate the expression levels of regulated on activation, normal T cell expressed and secreted (RANTES) mRNA and eotaxin mRNA in the nasal mucosa of toluene diisocyanate (TDI)-induced allergic rats and to evaluate which of them is primarily related to selective eosinophilic infiltration by comparing their expression levels with the numbers of infiltrated eosinophils and vascular cell adhesion molecule-1 (VCAM-1). MATERIAL AND METHODS We quantified the expression levels of two strong eosinophilic CC chemokines (RANTES and eotaxin) and VCAM-1 at mRNA levels in the nasal mucosa of TDI-induced allergic rats using competitive polymerase chain reaction and compared their expression levels with the number of infiltrated eosinophils. RESULTS The number of infiltrated eosinophils was significantly increased between 3 h and Day 4 in TDI-induced allergic rats, but had decreased by Day 5. VCAM-1 mRNA expression was also increased between 3 h and Day 4. The number of infiltrated eosinophils correlated with the expression levels of VCAM-1 mRNA (p < 0.01). In contrast, expression of RANTES mRNA and eotaxin mRNA was increased between 3 h and Day 2, peaked between Days 1 and 2 and then declined. Although the expression of both chemokines correlated with the numbers of infiltrated eosinophils (p < 0.01), peak expression levels of eotaxin mRNA were 14-fold higher than baseline levels whereas RANTES mRNA expression increased 3-fold.
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MESH Headings
- Animals
- Asthma/chemically induced
- Asthma/genetics
- Asthma/immunology
- Chemokine CCL11
- Chemokine CCL5/genetics
- Chemokines, CC/genetics
- Eosinophilia/chemically induced
- Eosinophilia/genetics
- Eosinophilia/immunology
- Gene Expression Regulation/drug effects
- Gene Expression Regulation/immunology
- Leukocyte Count
- Lymphocyte Activation/drug effects
- Lymphocyte Activation/genetics
- Lymphocyte Activation/immunology
- Male
- Nasal Mucosa/drug effects
- Nasal Mucosa/immunology
- RNA, Messenger/genetics
- Rats
- Rats, Sprague-Dawley
- Respiratory Hypersensitivity/chemically induced
- Respiratory Hypersensitivity/genetics
- Respiratory Hypersensitivity/immunology
- Reverse Transcriptase Polymerase Chain Reaction
- Rhinitis, Allergic, Perennial/chemically induced
- Rhinitis, Allergic, Perennial/genetics
- Rhinitis, Allergic, Perennial/immunology
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- Toluene 2,4-Diisocyanate/immunology
- Toluene 2,4-Diisocyanate/toxicity
- Vascular Cell Adhesion Molecule-1/genetics
- beta 2-Microglobulin/genetics
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Affiliation(s)
- Gi Jung Im
- Department of Otolaryngology--Head & Neck Surgery, College of Medicine, Sungbuk-Ku, Seoul, South Korea
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Lehner T, Wang Y, Whittall T, McGowan E, Kelly CG, Singh M. Functional domains of HSP70 stimulate generation of cytokines and chemokines, maturation of dendritic cells and adjuvanticity. Biochem Soc Trans 2005; 32:629-32. [PMID: 15270693 DOI: 10.1042/bst0320629] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/24/2023]
Abstract
Microbial HSP70 (heat-shock protein 70) consists of three functionally distinct domains: an N-terminal 44 kDa ATPase portion (amino acids 1-358), followed by an 18 kDa peptide-binding domain (amino acids 359-494) and a C-terminal 10 kDa fragment (amino acids 495-609). Immunological functions of these three different domains in stimulating monocytes and dendritic cells have not been fully defined. However, the C-terminal portion (amino acids 359-610) stimulates the production of CC chemokines, IL-12 (interleukin-12), TNFalpha(tumour necrosis factor alpha), NO and maturation of dendritic cells and also functions as an adjuvant in the induction of immune responses. In contrast, the ATPase domain of microbial HSP70 mostly lacks these functions. Since the receptor for HSP70 is CD40, which with its CD40 ligand constitutes a major co-stimulatory pathway in the interaction between antigen-presenting cells and T-cells, HSP70 may function as an alternative ligand to CD40L. HSP70-CD40 interaction has been demonstrated in non-human primates to play a role in HIV infection, in protection against Mycobacterium tuberculosis and in conversion of tolerance to immunity.
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Affiliation(s)
- T Lehner
- Mucosal Immunology Unit, Guy's, King's and St. Thomas' Hospital Medical and Dental Schools, London SE1 9RT, UK.
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Ness TL, Carpenter KJ, Ewing JL, Gerard CJ, Hogaboam CM, Kunkel SL. CCR1 and CC chemokine ligand 5 interactions exacerbate innate immune responses during sepsis. THE JOURNAL OF IMMUNOLOGY 2005; 173:6938-48. [PMID: 15557190 DOI: 10.4049/jimmunol.173.11.6938] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 11/19/2022]
Abstract
CCR1 has previously been shown to play important roles in leukocyte trafficking, pathogen clearance, and the type 1/type 2 cytokine balance, although very little is known about its role in the host response during sepsis. In a cecal ligation and puncture model of septic peritonitis, CCR1-deficient (CCR1(-/-)) mice were significantly protected from the lethal effects of sepsis when compared with wild-type (WT) controls. The peritoneal and systemic cytokine profile in CCR1(-/-) mice was characterized by a robust, but short-lived and regulated antibacterial response. CCR1 expression was not required for leukocyte recruitment, suggesting critical differences extant in the activation of WT and CCR1(-/-) resident or recruited peritoneal cells during sepsis. Peritoneal macrophages isolated from naive CCR1(-/-) mice clearly demonstrated enhanced cytokine/chemokine generation and antibacterial responses compared with similarly treated WT macrophages. CCR1 and CCL5 interactions markedly altered the inflammatory response in vivo and in vitro. Administration of CCL5 increased sepsis-induced lethality in WT mice, whereas neutralization of CCL5 improved survival. CCL5 acted in a CCR1-dependent manner to augment production of IFN-gamma and MIP-2 to damaging levels. These data illustrate that the interaction between CCR1 and CCL5 modulates the innate immune response during sepsis, and both represent potential targets for therapeutic intervention.
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MESH Headings
- Animals
- Ascitic Fluid/cytology
- Ascitic Fluid/immunology
- Ascitic Fluid/pathology
- Cecum
- Chemokine CCL5/biosynthesis
- Chemokine CCL5/deficiency
- Chemokine CCL5/genetics
- Chemokine CCL5/physiology
- Chemokines/biosynthesis
- Chemotaxis, Leukocyte/genetics
- Chemotaxis, Leukocyte/immunology
- Colony Count, Microbial
- Cytokines/biosynthesis
- Female
- Genetic Predisposition to Disease
- Immunity, Innate
- Ligation
- Macrophages, Peritoneal/immunology
- Macrophages, Peritoneal/metabolism
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Knockout
- NF-kappa B/metabolism
- Peritonitis/genetics
- Peritonitis/immunology
- Peritonitis/microbiology
- Peritonitis/mortality
- Punctures
- Receptors, CCR1
- Receptors, Chemokine/deficiency
- Receptors, Chemokine/genetics
- Receptors, Chemokine/physiology
- Sepsis/genetics
- Sepsis/immunology
- Sepsis/microbiology
- Sepsis/mortality
- Up-Regulation/genetics
- Up-Regulation/immunology
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Affiliation(s)
- Traci L Ness
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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Yanaba K, Mukaida N, Matsushima K, Murphy PM, Takehara K, Sato S. Role of C-C chemokine receptors?1 and?5 and CCL3/macrophage inflammatory protein-1? in the cutaneous Arthus reaction: possible attenuation of their inhibitory effects by compensatory chemokine production. Eur J Immunol 2004; 34:3553-61. [PMID: 15517609 DOI: 10.1002/eji.200425426] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/13/2022]
Abstract
The deposition of immune complexes induces an acute inflammatory response with tissue injury. Immune complex-induced tissue injury is mediated by inflammatory cell infiltration that is highly regulated by multiple chemokines. To assess the role of the chemokine receptors CCR1 and CCR5, and a ligand for these receptors CCL3/macrophage inflammatory protein-1alpha, in this pathogenic process, the reverse passive cutaneous Arthus reaction was induced in mice lacking CCR1, CCR5, or CCL3. Edema was significantly attenuated in CCR1-deficient (CCR1(-/-)) and CCL3(-/-) mice but not CCR5(-/-) mice, compared with wild-type mice. Numbers of infiltrating neutrophils and mast cells were reduced in CCL3(-/-) and CCR1(-/-) mice, respectively, compared with wild-type mice. CCR1 and CCR5 were expressed on neutrophils and mast cells. Remarkably, the intradermal mRNA expression of CCL5/RANTES, another ligand for CCR1 and CCR5, was increased in CCR5(-/-) and CCL3(-/-) mice, compared with wild-type mice, while the cutaneous CCL3 mRNA expression was augmented in CCR1(-/-) and CCR5(-/-) mice. These results indicate that CCR1, CCR5, and CCL3 cooperatively contribute to the cutaneous Arthus reaction, and also suggest that enhanced expression of CCL3 and CCL5 compensates for the loss of CCR1, CCR5, and CCL3 in the reaction.
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Affiliation(s)
- Koichi Yanaba
- Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
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Liu J, Xiang Z, Ma X. Role of IFN regulatory factor-1 and IL-12 in immunological resistance to pathogenesis of N-methyl-N-nitrosourea-induced T lymphoma. THE JOURNAL OF IMMUNOLOGY 2004; 173:1184-93. [PMID: 15240709 DOI: 10.4049/jimmunol.173.2.1184] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 11/19/2022]
Abstract
IFN regulatory factor-1 (IRF-1) is a critical effector molecule in IFN signaling and acts as a tumor suppressor and tumor susceptibility gene. IL-12 is a key factor in the induction of innate resistance and generation of Th1 cells and CTL. Our recent study has revealed an intimate relationship between IRF-1 and IL-12 in that IRF-1 regulates the production of IL-12 by selectively controlling transcriptional activation of IL-12 p35 gene. In this work, we find that IRF-1-deficient mice are highly susceptible to N-methyl-N-nitrosourea (MNU)-induced T lymphomas. This susceptibility is associated with strong defects in the expression of IL-12, lymphotoxin (LT)beta, and IFN-gamma. Consistently, IL-12 p35(-/-), IFN-gamma(-/-), and LTbeta(-/-) mice are also highly vulnerable to MNU-induced carcinogenesis. Administration of rIL-12 to IRF-1(-/-) mice restores normal expression of LTbeta and IFN-gamma, and significantly enhances the ability of IRF-1(-/-) mice to resist MNU-induced pathogenesis. This strongly suggests an IRF-1/IL-12/IFN-gamma regulatory axis in tumor surveillance. By DNA microarray analysis, we comprehensively identify differences and patterns in gene expression in splenocytes of wild-type (WT) vs IRF-1(-/-) mice challenged with MNU. This study contributes to efforts to elucidate the cellular/molecular mechanisms and the downstream players involved in IRF-1-mediated host defense against lymphoproliferative malignancies.
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Affiliation(s)
- Jianguo Liu
- Department of Microbiology and Immunology, Weill Medical College, Cornell University, 1300 York Avenue, New York, NY 10021, USA
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40
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Lehner T, Stanford MR, Phipps PA, Sun JB, Xiao BG, Holmgren J, Shinnick T, Hasan A, Mizushima Y. Immunopathogenesis and prevention of uveitis with the Behçet's disease-specific peptide linked to cholera toxin B. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2003; 528:173-80. [PMID: 12918685 DOI: 10.1007/0-306-48382-3_34] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 03/04/2023]
Affiliation(s)
- T Lehner
- Guy's, King's and St Thomas' Hospital Medical School, Kings College, London, England
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41
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Sonoda KH, Sasa Y, Qiao H, Tsutsumi C, Hisatomi T, Komiyama S, Kubota T, Sakamoto T, Kawano YI, Ishibashi T. Immunoregulatory role of ocular macrophages: the macrophages produce RANTES to suppress experimental autoimmune uveitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2003; 171:2652-9. [PMID: 12928419 DOI: 10.4049/jimmunol.171.5.2652] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 01/07/2023]
Abstract
Murine experimental autoimmune uveitis (EAU) is a model of human uveitis. Ocular-infiltrating macrophages play a crucial role in the generation of tissue damage in EAU. In fact, several chemokines are actually produced in the inflamed eye. The aim of this study was to elucidate the role of ocular macrophage-derived chemokines in EAU. C57BL/6 mice were immunized with human interphotoreceptor retinoid binding protein peptide 1-20, and the EAU severity was scored at multiple time points based on microscopic fundus observations (retinal vascular dilatation and exudates) and histological examinations. The peak inflammatory response was observed 1 wk (day 16) after the beginning of macrophage infiltration to the eye (day 9). Ocular-infiltrating cells were enriched or depleted of macrophages by magnetic beads and analyzed by real-time RT-PCR for chemokine mRNA production. We found that only the macrophage-enriched cells from the eye produced RANTES, and thus proposed that macrophage-derived RANTES facilitated the ocular inflammations. In contrast to our postulate, neutralization of RANTES by specific Ab in vivo on days 9 and 13 exacerbated EAU. We also found that the ratio of ocular CD4/CD8 T cells was markedly increased after treatment. As a result, RANTES neutralization might exacerbate EAU by modulating the type of T cell subsets recruited to the eye. In conclusion, our data provide insight into the immunoregulatory role of macrophages and RANTES in the pathogenesis of ocular inflammation. Not all macrophage-derived chemokines cause local inflammation, since RANTES produced by ocular macrophages appears to suppress EAU.
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Affiliation(s)
- Koh-Hei Sonoda
- Department of Ophthalmology, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
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42
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Di Gioacchino M, Verna N, Cavallucci E, Paolini F, Caruso R, Grana M, Schiavone C, Di Iorio A, Ramondo S, Reale M, Paganelli R, Theoharides TC. Steroid and antihistamines modulate RANTES release in cultured peripheral blood mononuclear cells of atopic patients. Int J Immunopathol Pharmacol 2002; 15:27-34. [PMID: 12593785 DOI: 10.1177/039463200201500104] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/22/2023] Open
Abstract
RANTES plays a crucial role in cell recruitment in allergic inflammation. We investigated the pharmacological modulation of RANTES release in cultured peripheral blood mononuclear cells obtained from allergic patients with active asthma. Chemokine production was assessed before and after 15 day treatment with histamine-1 receptor antagonists (antihistamines) (Loratadine or Cetirizine) and a steroid (Deflazacort), both in unstimulated and PHA-stimulated cell cultures. Results were compared with those obtained from placebo-treated patients. During the treatment period, patients recorded morning and evening peak expiratory flow (PEF) by the mini-Wright procedure. PEF absolute values and diurnal variability significantly improved respect to the pre-treatment in steroid-treated patients, in comparison to the placebo and antihistamine-treated groups (p<0.001 and 0.01, respectively). PEF diurnal variability in the antihistamine-treated group were lower than placebo-treated group without statistical significance (p=0.06). No differences could be found in RANTES levels in supernatants of all cultures between the two antihistamines. RANTES release significantly decreased in supernatants of all cell cultures from steroid (p<0.01) and antihistamine (p=0.03 and 0.04) groups after treatments, compared to the basal values; whereas it increased slightly in controls. Co-variance analysis on RANTES levels, adjusting for pre-treatment values, showed a significant reduction of RANTES release by PHA-stimulated PBMCs from steroid (p=0.003) and anti-histamine (p=0.03) groups, with respect to the placebo group. The same statistical tool applied between the steroid and the antihistamine groups showed, after therapy, the lowest levels of RANTES to be associated with steroid treatment (p=0.005). The study shows that the steroid is the most effective drug in modulating RANTES release from PBMCs. However, antihistamines, which are able to reduce cell recruitment due to chemokine release, avoiding important side effects, may be useful in long term therapy in controlling and preventing allergic inflammation.
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Affiliation(s)
- M. Di Gioacchino
- Dept. Medicine and Science of Ageing, University of Chieti, School of Medicine, Chieti, Italy
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43
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Abstract
The prevalence of asthma has risen drastically in the last two decades, with a worldwide impact on health care systems. Although several factors contribute to the development of asthma, inflammation seems to be a common factor that leads to the most severe asthmatic responses. In the past decade, researchers have characterized a large group of chemotactic cytokines, also known as chemokines, which are implicated in asthmatic inflammation. These chemokines control and direct the migration and activation of various leukocyte populations. Targeting chemokines should lead to new ways of controlling the inflammatory asthmatic response.
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Affiliation(s)
- N W Lukacs
- University of Michigan Medical School, Department of Pathology, Ann Arbor, Michigan 48109-0602, USA.
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44
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Hill PB, Olivry T. The ACVD task force on canine atopic dermatitis (V): biology and role of inflammatory cells in cutaneous allergic reactions. Vet Immunol Immunopathol 2001; 81:187-98. [PMID: 11553379 DOI: 10.1016/s0165-2427(01)00310-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/27/2022]
Abstract
Numerous inflammatory cells are thought to play a role in the pathogenesis of canine atopic dermatitis (AD) although, in the past, mast cells were considered the most important. However, evidence for this assumption is lacking. In this paper, we review the literature concerning the role of inflammatory cells in allergic reactions and conclude that a complex interplay exists between a wide variety of cell types. Thus, on the basis of the available evidence, the cells that appear to be the most important in the pathogenesis of canine AD are Langerhans' cells and dermal dendritic cells (both responsible for antigen processing and presentation), B-lymphocytes (responsible for reaginic antibody production), allergen-specific helper T-lymphocytes (responsible for cytokine production leading to activation of B-cells and other inflammatory cells) and mast cells (production of inflammatory mediators leading to inflammation).
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Affiliation(s)
- P B Hill
- Department of Veterinary Clinical Studies, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Hospital for Small Animals, Easter Bush Veterinary Centre, Roslin, Edinburgh EH25 9RG, Scotland, UK.
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45
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Abstract
The activity of the chemokine RANTES is not restricted merely to chemotaxis. It is a powerful leukocyte activator, a feature potentially relevant in a range of inflammatory disorders. RANTES has attracted attention because it can potently suppress and, in some circumstances, enhance HIV replication. These characteristics are critically dependent on its ability to self-aggregate and bind to glycosaminoglycans.
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Affiliation(s)
- V Appay
- Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, OX3 9DS, Oxford, UK.
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46
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Reale M, Barbacane RC, DiGioacchino M, Felaco M, Croce A, Ferro FM, Lotti TM, Conti P. Differential expression and secretion of RANTES and MCP-1 in activated peripheral blood mononuclear cell cultures of atopic subjects. Immunol Lett 2001; 76:7-14. [PMID: 11222907 DOI: 10.1016/s0165-2478(00)00320-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/17/2022]
Abstract
RANTES and MCP-1 represent a link between the activation of monocytes, lymphocytes, basophils, mast cells and eosinophils in inflammatory disorders, such as the late phase allergic reaction. These C-C chemokines also play a role in regulating Th cell cytokine production and leukocyte trafficking. In this study, we determined the expression and secretion of RANTES and MCP-1 from PHA-activated PBMC of healthy and atopic subjects with no symptoms. Levels of RANTES from PHA-activated PBMC of atopic patients were higher, at 18 and 24 h incubations (42+/-5.5 and 48+/-4), compared to controls (20+/-4 and 35+/-4), respectively; while MCP-1 was not (12+/-3 and 17+/-3) compared to controls (10.5+/-3 and 15+/-2), respectively. This effect was also revealed on RANTES mRNA expression, as determined by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. In addition, PHA-activated PBMC of atopic subjects produce more IL-4 (five times more) than healthy subjects, while IFN-gamma did not vary. RANTES, compared to MCP-1, may have more influence on signal transduction pathways, either in physiologic or inflammatory states and may induce profound effects on the regulation of cell activity. The differential production of RANTES and MCP-1 may lead to diverse regulation of the function and development of cells involved in the allergic response. These studies emphasize the importance of chemokine selectivity during inflammation.
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Affiliation(s)
- M Reale
- Department of Oncology and Neurosciences, Immunology Division, School of Medicine, University of Chieti, Via dei Vestini, 66013, Chieti, Italy
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47
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Ajuebor MN, Hogaboam CM, Kunkel SL, Proudfoot AE, Wallace JL. The chemokine RANTES is a crucial mediator of the progression from acute to chronic colitis in the rat. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2001; 166:552-8. [PMID: 11123336 DOI: 10.4049/jimmunol.166.1.552] [Citation(s) in RCA: 116] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/13/2022]
Abstract
Chemokines have well characterized proinflammatory actions, including the ability to induce extravasation of leukocytes that participate in chronic inflammation. In this study, we evaluated the role of a C-C chemokine, RANTES, in the chronic phase of a rat model of colitis. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid. At various timepoints thereafter (2 h to 14 days), colonic tissue levels of several chemokines were measured. Unlike the expression of monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and cytokine-induced neutrophil chemoattractant, the expression of RANTES was significantly elevated during the chronic phase of colitis (> or =7 days after induction). Colonic RANTES mRNA expression was also significantly elevated during the chronic phase of colitis. The numbers of macrophages and monocytes in the colonic mucosa increased substantially during the chronic phase, as did expression of two of the receptors (CCR1 and CCR5) to which RANTES is known to bind. Administration on days 7 through 14 after trinitrobenzene sulfonic acid administration of a CCR1/CCR5 receptor antagonist, Met-RANTES, resulted in a significant reduction of both macroscopic and microscopic colonic damage, as well as reducing the recruitment into the colon of monocytes, mast cells, and neutrophils. In some rats, treatment with Met-RANTES resulted in a near-complete resolution of colonic damage and inflammation. These results suggest a crucial role of RANTES in the progression from acute to chronic inflammation in a rat model of colitis.
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MESH Headings
- Acute Disease
- Administration, Rectal
- Animals
- Cell Movement/drug effects
- Cell Movement/immunology
- Chemokine CCL5/administration & dosage
- Chemokine CCL5/analogs & derivatives
- Chemokine CCL5/biosynthesis
- Chemokine CCL5/pharmacology
- Chemokine CCL5/physiology
- Chronic Disease
- Colitis/etiology
- Colitis/immunology
- Colitis/pathology
- Colitis/prevention & control
- Disease Progression
- Dose-Response Relationship, Drug
- Haptens/administration & dosage
- Inflammation Mediators/administration & dosage
- Inflammation Mediators/physiology
- Injections, Intravenous
- Leukocyte Count
- Male
- Mast Cells/immunology
- Mast Cells/pathology
- Monocytes/immunology
- Monocytes/pathology
- RNA, Messenger/biosynthesis
- Rats
- Rats, Wistar
- Receptors, CCR1
- Receptors, CCR5/biosynthesis
- Receptors, CCR5/genetics
- Receptors, Chemokine/biosynthesis
- Receptors, Chemokine/genetics
- Time Factors
- Trinitrobenzenesulfonic Acid/administration & dosage
- Trinitrobenzenesulfonic Acid/immunology
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Affiliation(s)
- M N Ajuebor
- Mucosal Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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48
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Sin J, Kim JJ, Pachuk C, Satishchandran C, Weiner DB. DNA vaccines encoding interleukin-8 and RANTES enhance antigen-specific Th1-type CD4(+) T-cell-mediated protective immunity against herpes simplex virus type 2 in vivo. J Virol 2000; 74:11173-80. [PMID: 11070014 PMCID: PMC113206 DOI: 10.1128/jvi.74.23.11173-11180.2000] [Citation(s) in RCA: 107] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/12/2023] Open
Abstract
Chemokines are inflammatory molecules that act primarily as chemoattractants and as activators of leukocytes. Their role in antigen-specific immune responses is of importance, but their role in disease protection is unknown. Recently it has been suggested that chemokines modulate immunity along more classical Th1 and Th2 phenotypes. However, no data currently exist in an infectious challenge model system. We analyzed the modulatory effects of selected chemokines (interleukin-8 [IL-8], gamma interferon-inducible protein 10 [IP-10], RANTES, monocyte chemotactic protein 1 [MCP-1], and macrophage inflammatory protein 1 alpha [MIP-1 alpha]) on immune phenotype and protection against lethal challenge with herpes simplex virus type 2 (HSV-2). We observed that coinjection with IL-8 and RANTES plasmid DNAs dramatically enhanced antigen-specific Th1 type cellular immune responses and protection from lethal HSV-2 challenge. This enhanced protection appears to be mediated by CD4(+) T cells, as determined by in vitro and in vivo T-cell subset deletion. Thus, IL-8 and RANTES cDNAs used as DNA vaccine adjuvants drive antigen-specific Th1 type CD4(+) T-cell responses, which result in reduced HSV-2-derived morbidity, as well as reduced mortality. However, coinjection with DNAs expressing MCP-1, IP-10, and MIP-1 alpha increased mortality in the challenged mice. Chemokine DNA coinjection also modulated its own production as well as the production of cytokines. These studies demonstrate that chemokines can dominate and drive immune responses with defined phenotypes, playing an important role in the generation of protective antigen-specific immunity.
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Affiliation(s)
- J Sin
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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49
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Pan ZZ, Parkyn L, Ray A, Ray P. Inducible lung-specific expression of RANTES: preferential recruitment of neutrophils. Am J Physiol Lung Cell Mol Physiol 2000; 279:L658-66. [PMID: 11000125 DOI: 10.1152/ajplung.2000.279.4.l658] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/22/2023] Open
Abstract
The chemokine regulated on activation normal T cells expressed and secreted (RANTES) has been implicated in eosinophil chemotaxis in asthma and allergic diseases, which are thought to be T helper (Th) type 2-dominated diseases. However, adoptive transfer of Th1 cells in mice upregulates RANTES gene expression in the lung, and increased RANTES expression has been documented in several Th1 cell-dominated conditions that are associated with neutrophilia. The in vivo role of RANTES in the pathogenesis of disease processes is not well understood. To determine the effect of RANTES expression alone in vivo, we generated transgenic mice that overexpress RANTES specifically in the lung in an inducible fashion. The airways of the transgenic mice overexpressing RANTES displayed a significant increase in neutrophil infiltration compared with that in control mice. The increased airway neutrophilia was also evident when the transgenic mice were tested in a murine model of allergic airway inflammation. RANTES expression also induced expression of the chemokine genes macrophage inflammatory protein-2, 10-kDa interferon-gamma-inducible protein, and monocyte chemoattractant protein-1 in the lungs of the transgenic mice. Our studies highlight a hitherto unappreciated role for RANTES in neutrophil trafficking during inflammation. Thus increased RANTES expression, as observed during respiratory viral infections, may play an important role in the associated neutrophilia and exacerbations of asthma.
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Affiliation(s)
- Z Z Pan
- Pulmonary and Critical Care Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA
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50
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Lee AH, Hong JH, Seo YS. Tumour necrosis factor-alpha and interferon-gamma synergistically activate the RANTES promoter through nuclear factor kappaB and interferon regulatory factor 1 (IRF-1) transcription factors. Biochem J 2000; 350 Pt 1:131-8. [PMID: 10926836 PMCID: PMC1221234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/17/2023]
Abstract
Inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) synergistically activate expression of the RANTES (regulated upon activation, normal T-cell expressed and secreted) gene, which plays a crucial role in the chemoattraction of leukocytes during the inflammatory response. To understand at the molecular level the mechanism by which the two cytokines activate RANTES gene expression, we determined the requirement of cis-acting elements in the RANTES promoter and trans-acting factors. The murine RANTES promoter contained one putative interferon regulatory factor, IRF, and three putative nuclear factor kappaB (NF-kappaB) binding sites. Specific destruction of the IRF binding site and one of the three NF-kappaB binding sites abolished the inducibility of promoter activity by IFN-gamma and TNF-alpha, respectively. In contrast, mutation of the other two putative NF-kappaB binding sites did not affect RANTES promoter activity significantly. In addition, the RANTES promoter was stimulated by co-transfection of plasmids that expressed either p65, an NF-kappaB family protein, or the IRF-1 transcription factor. RANTES promoters with mutations in the NF-kappaB or IRF binding sites were not stimulated by p65 or IRF-1 expression, respectively. In electrophoretic mobility-shift and immunologic assays, we showed that IRF-1 was induced after cells were treated with IFN-gamma and that NF-kappaB was activated by TNF-alpha treatment. These results demonstrate that both NF-kappaB and IRF-1 transcription factors mediate the induction of RANTES expression via their cognate cis-acting elements when cells are stimulated by TNF-alpha and IFN-gamma.
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Affiliation(s)
- A H Lee
- National Creative Research Initiative Center for Cell Cycle Control, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 300 Chunchun-Dong, Changan-Ku, Suwon-Si, Kyunggi-Do, 440-746, South Korea
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