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1
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Jin C, Wu S, Liang Z, Zhang J, Lei X, Bai H, Liang G, Su X, Chen X, Wang P, Wang Y, Guan L, Yao J. Multi-omics reveal mechanisms of high enteral starch diet mediated colonic dysbiosis via microbiome-host interactions in young ruminant. MICROBIOME 2024; 12:38. [PMID: 38395946 PMCID: PMC10893732 DOI: 10.1186/s40168-024-01760-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 01/08/2024] [Indexed: 02/25/2024]
Abstract
BACKGROUND Although rumen development is crucial, hindgut undertakes a significant role in young ruminants' physiological development. High-starch diet is usually used to accelerate rumen development for young ruminants, but always leading to the enteral starch overload and hindgut dysbiosis. However, the mechanism behind remains unclear. The combination of colonic transcriptome, colonic luminal metabolome, and metagenome together with histological analysis was conducted using a goat model, with the aim to identify the potential molecular mechanisms behind the disrupted hindgut homeostasis by overload starch in young ruminants. RESULT Compared with low enteral starch diet (LES), high enteral starch diet (HES)-fed goats had significantly higher colonic pathology scores, and serum diamine oxidase activity, and meanwhile significantly decreased colonic mucosal Mucin-2 (MUC2) protein expression and fecal scores, evidencing the HES-triggered colonic systemic inflammation. The bacterial taxa Prevotella sp. P4-67, Prevotella sp. PINT, and Bacteroides sp. CAG:927, together with fungal taxa Fusarium vanettenii, Neocallimastix californiae, Fusarium sp. AF-8, Hypoxylon sp. EC38, and Fusarium pseudograminearum, and the involved microbial immune pathways including the "T cell receptor signaling pathway" were higher in the colon of HES goats. The integrated metagenome and host transcriptome analysis revealed that these taxa were associated with enhanced pathogenic ability, antigen processing and presentation, and stimulated T helper 2 cell (TH2)-mediated cytokine secretion functions in the colon of HES goats. Further luminal metabolomics analysis showed increased relative content of chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA), and decreased the relative content of hypoxanthine in colonic digesta of HES goats. These altered metabolites contributed to enhancing the expression of TH2-mediated inflammatory-related cytokine secretion including GATA Binding Protein 3 (GATA3), IL-5, and IL-13. Using the linear mixed effect model, the variation of MUC2 biosynthesis explained by the colonic bacteria, bacterial functions, fungi, fungal functions, and metabolites were 21.92, 20.76, 19.43, 12.08, and 44.22%, respectively. The variation of pathology scores explained by the colonic bacterial functions, fungal functions, and metabolites were 15.35, 17.61, and 57.06%. CONCLUSIONS Our findings revealed that enteral starch overload can trigger interrupted hindgut host-microbiome homeostasis that led to impaired mucosal, destroyed colonic water absorption, and TH2-mediated inflammatory process. Except for the colonic metabolites mostly contribute to the impaired mucosa, the nonnegligible contribution from fungi deserves more future studies focused on the fungal functions in hindgut dysbiosis of young ruminants. Video Abstract.
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Affiliation(s)
- Chunjia Jin
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Shengru Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China.
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Ziqi Liang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Jun Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Xinjian Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Hanxun Bai
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Gaofeng Liang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Xiaodong Su
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Xiaodong Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Peiyue Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Yue Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Leluo Guan
- Department of Agricultural, Food and Nutritional Science, University of Alberta, 116 St. and 85 Ave., Edmonton, AB, T6G 2P5, Canada.
| | - Junhu Yao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, People's Republic of China.
- Key Laboratory of Livestock Biology, Northwest A&F University, Yangling, 712100, Shaanxi, China.
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2
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Hu C, Liao S, Lv L, Li C, Mei Z. Intestinal Immune Imbalance is an Alarm in the Development of IBD. Mediators Inflamm 2023; 2023:1073984. [PMID: 37554552 PMCID: PMC10406561 DOI: 10.1155/2023/1073984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/06/2023] [Accepted: 07/08/2023] [Indexed: 08/10/2023] Open
Abstract
Immune regulation plays a crucial role in human health and disease. Inflammatory bowel disease (IBD) is a chronic relapse bowel disease with an increasing incidence worldwide. Clinical treatments for IBD are limited and inefficient. However, the pathogenesis of immune-mediated IBD remains unclear. This review describes the activation of innate and adaptive immune functions by intestinal immune cells to regulate intestinal immune balance and maintain intestinal mucosal integrity. Changes in susceptible genes, autophagy, energy metabolism, and other factors interact in a complex manner with the immune system, eventually leading to intestinal immune imbalance and the onset of IBD. These events indicate that intestinal immune imbalance is an alarm for IBD development, further opening new possibilities for the unprecedented development of immunotherapy for IBD.
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Affiliation(s)
- Chunli Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Shengtao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Chuanfei Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Zhechuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
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3
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Miyazu T, Ishida N, Asai Y, Tamura S, Tani S, Yamade M, Hamaya Y, Iwaizumi M, Osawa S, Furuta T, Baba S, Sugimoto K. Importance of eosinophilic infiltration of the colonic mucosa in ulcerative colitis patients who are refractory to maintenance therapy: A prospective, single-center study. Medicine (Baltimore) 2022; 101:e31017. [PMID: 36221337 PMCID: PMC9542815 DOI: 10.1097/md.0000000000031017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Eosinophilic infiltration is sometimes observed histologically in ulcerative colitis (UC), but the effect of the degree of infiltration on the treatment course for UC is not completely understood. We investigated whether short-term steroid administration in UC patients refractory to maintenance therapy, with high eosinophilic infiltration in the colonic mucosa, contributed to the clinical and endoscopic improvement. Ten patients with endoscopically active and pathologically high eosinophilic infiltration, based on pathological examination using endoscopic biopsy, were examined for the clinical background when starting steroid treatment. The clinical and endoscopic improvement before and after steroid use were assessed prospectively. The average initial steroid dosage and duration of use were 21.0 mg and 102.7 days, respectively. The mean values before and after steroid use of the clinical activity index, the Mayo endoscopic subscore, and the UC endoscopic index of severity were 2.4 and 1.0, 1.8 and 0.7, and 3.9 and 1.1, respectively. All scores improved significantly after steroid use (P = .042, P = .002, P = .002, respectively). Steroids were discontinued in all patients; no patients required steroid re-administration. There may be cases of UC with eosinophilic infiltration into the colonic mucosa and resistance to maintenance treatment, suggesting that short-term steroid administration may contribute to clinical and endoscopic improvements.
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Affiliation(s)
- Takahiro Miyazu
- First Department of Medicine, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Natsuki Ishida
- First Department of Medicine, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Yusuke Asai
- First Department of Medicine, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Satoshi Tamura
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Shinya Tani
- First Department of Medicine, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Moriya Iwaizumi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Satoshi Baba
- Department of Diagnostic Pathology, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Handayama, Higashi-ku, Hamamatsu, Japan
- *Correspondence: Ken Sugimoto, First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan (e-mail: )
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4
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The Therapeutic Role of Short-Chain Fatty Acids Mediated Very Low-Calorie Ketogenic Diet-Gut Microbiota Relationships in Paediatric Inflammatory Bowel Diseases. Nutrients 2022; 14:nu14194113. [PMID: 36235765 PMCID: PMC9572225 DOI: 10.3390/nu14194113] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 12/02/2022] Open
Abstract
The very low-calorie ketogenic diet (VLCKD) has been recognized as a promising dietary regimen for the treatment of several diseases. Short-chain fatty acids (SCFAs) produced by anaerobic bacterial fermentation of indigestible dietary fibre in the gut have potential value for their underlying epigenetic role in the treatment of obesity and asthma-related inflammation through mediating the relationships between VLCKD and the infant gut microbiota. However, it is still unclear how VLCKD might influence gut microbiota composition in children, and how SCFAs could play a role in the treatment of inflammatory bowel disease (IBD). To overcome this knowledge gap, this review aims to investigate the role of SCFAs as key epigenetic metabolites that mediate VLCKD-gut microbiota relationships in children, and their therapeutic potential in IBD.
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5
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Aghamohammad S, Sepehr A, Miri ST, Najafi S, Pourshafie MR, Rohani M. The potential role of Bifidobacterium spp. as a preventive and therapeutic agent in controlling inflammation via affecting inflammatory signalling pathways. Lett Appl Microbiol 2022; 75:1254-1263. [PMID: 35876252 DOI: 10.1111/lam.13793] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/11/2022] [Accepted: 07/19/2022] [Indexed: 11/26/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease with relapses and periods of remission. Forasmuch as, dysregulation of the immune system is one of the triggers of IBD, taking probiotics as one of the immunomodulators in the gut, could help to control inflammation and IBD via influencing signalling pathways. Here, we aimed to investigate the efficacy of five selected Bifidobacterium strains in modulating JAK/STAT and NF-kB inflammatory signalling pathways via using the in vitro assay. A quantitative real-time polymerase chain reaction assay was used to analyse the expression of JAK/STAT and inflammatory genes followed by potential probiotic treatments before, after and simultaneously with the inflammation induction (sonicated pathogen). The production of IL-6 and IL-1β after probiotic treatment was evaluated. Probiotic treatment resulted in the downregulation of TIRAP, IRAK4, NEMO and RIP genes in the NF-kB pathway, as well as JAK genes compared to sonicate-treated cells. The expression of STAT genes was different after our selected Bifidobacterium strains treatment. The production of IL-6 and IL-1β decreased after probiotic treatment. These strains of Bifidobacterium spp. showed anti-inflammatory effects on HT-29 cells via modulation of JAK/STAT and NF-kB signalling pathways. The use of Bifidobacterium spp. could be considered as a suitable preventive and complementary treatment for patients with inflammatory bowel disease.
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Affiliation(s)
- S Aghamohammad
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
| | - A Sepehr
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
| | - S T Miri
- Department of Biology, Science and Research Branch Islamic Azad University, Tehran, Iran
| | - S Najafi
- Department of Biology, Science and Research Branch Islamic Azad University, Tehran, Iran
| | - M R Pourshafie
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
| | - M Rohani
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
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6
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Yin X, Ge J, Ge X, Gao J, Su X, Wang X, Zhang Q, Wang Z. MiR-363-5p modulates regulatory T cells through STAT4-HSPB1-Notch1 axis and is associated with the immunological abnormality in Graves' disease. J Cell Mol Med 2021; 25:9364-9377. [PMID: 34431214 PMCID: PMC8500983 DOI: 10.1111/jcmm.16876] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/24/2021] [Accepted: 08/09/2021] [Indexed: 12/21/2022] Open
Abstract
MiRNAs are a class of small non-coding RNAs with ability to regulate function of Treg cells and are involved in many autoimmune diseases. Our previous study found that miR-363-5p expression was significantly upregulated in peripheral Treg cells of GD patients. Herein, we aimed to investigate its effect and mechanism on Treg cell dysfunction in GD patients. The results showed that miR-363-5p upregulation was significantly associated with the Treg cell dysfunction and inflammatory factors levels in GD patients. Transcriptome sequencing revealed that 883 genes were significantly regulated by miR-363-5p in Treg cells. These genes with significant differential expression were primarily involved in lymphocyte differentiation, immunity, as well as Notch1 and various interleukin signalling pathways. Moreover, miR-363-5p can regulate HSPB1 and Notch1 through the target gene STAT4, thereby regulating Notch1 signalling pathway and inhibiting Treg cells. The effects of miR-363-5p on Treg cell function and STAT4-HSPB1-Notch1 axis were also verified in GD patients. In conclusion, our results indicated that miR-363 could inhibit the proliferation, differentiation and function of Treg cells by regulating the STAT4-HSPB1-Notch1 axis through target gene STAT4. MiR-363-5p may play an important role in Treg cell dysfunction and immune tolerance abnormalities in GD patients.
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Affiliation(s)
- Xianlun Yin
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Junfeng Ge
- Department of AnesthesiologyJinan Second People's HospitalJinanShandongChina
| | - Xiurong Ge
- Division of Endocrinology and MetabolismDivision of GeriatricsShandong Provincial HospitalCheeloo College of MedicineShandong Provincial Key Laboratory of Endocrinology and Lipid MetabolismShandong Institute of Endocrine and Metabolic DiseaseShandong UniversityJinanChina
| | - Jing Gao
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Xinhuan Su
- Division of Endocrinology and MetabolismDivision of GeriatricsShandong Provincial HospitalCheeloo College of MedicineShandong Provincial Key Laboratory of Endocrinology and Lipid MetabolismShandong Institute of Endocrine and Metabolic DiseaseShandong UniversityJinanChina
| | - Xiaowei Wang
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Qunye Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function ResearchChinese Ministry of EducationChinese National Health Commission and Chinese Academy of Medical SciencesThe State and Shandong Province Joint Key Laboratory of Translational Cardiovascular MedicineDepartment of CardiologyQilu HospitalCheeloo College of MedicineShandong UniversityJinanChina
| | - Zhe Wang
- Division of Endocrinology and MetabolismDivision of GeriatricsShandong Provincial HospitalCheeloo College of MedicineShandong Provincial Key Laboratory of Endocrinology and Lipid MetabolismShandong Institute of Endocrine and Metabolic DiseaseShandong UniversityJinanChina
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7
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Abstract
The Janus kinase (JAK), signal transducer of activation (STAT) pathway, discovered by investigating interferon gene induction, is now recognized as an evolutionary conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. Since its discovery, this pathway has become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors such as cytokines and hormones, mediate their diverse functions. The understanding of JAK-STAT signaling in the intestine has not only impacted basic science research, particularly in the understanding of intercellular communication and cell-extrinsic control of gene expression, but it has also become a prototype for transition of bench to bedside research, culminating in the clinical implementation of pathway-specific therapeutics.
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8
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Giannoudaki E, Gargan S, Hussey S, Long A, Walsh PT. Opportunities to Target T Cell Trafficking in Pediatric Inflammatory Bowel Disease. Front Pediatr 2021; 9:640497. [PMID: 33816403 PMCID: PMC8012547 DOI: 10.3389/fped.2021.640497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
T cell subsets are considered central orchestrators of inflammation and homeostasis in the intestine and are established targets for the treatment of inflammatory bowel disease. While approaches aimed at the neutralization of T cell effector cytokines have provided significant benefits for pediatric and adult patients, more recent strategies aimed at inhibiting the infiltration of pathogenic T cell subsets have also emerged. In this review, we describe current knowledge surrounding the function of T cell subsets in pediatric inflammatory bowel disease and outline approaches aimed at targeting T cell trafficking to the intestine which may represent a new treatment option for pediatric inflammatory bowel disease.
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Affiliation(s)
- Eirini Giannoudaki
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Siobhan Gargan
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Seamus Hussey
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Department of Paediatrics, Royal College of Surgeons of Ireland, Dublin, Ireland
| | - Aideen Long
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Patrick T Walsh
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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9
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Gamez-Belmonte R, Erkert L, Wirtz S, Becker C. The Regulation of Intestinal Inflammation and Cancer Development by Type 2 Immune Responses. Int J Mol Sci 2020; 21:ijms21249772. [PMID: 33371444 PMCID: PMC7767427 DOI: 10.3390/ijms21249772] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
The gut is among the most complex organs of the human body. It has to exert several functions including food and water absorption while setting up an efficient barrier to the outside world. Dysfunction of the gut can be life-threatening. Diseases of the gastrointestinal tract such as inflammatory bowel disease, infections, or colorectal cancer, therefore, pose substantial challenges to clinical care. The intestinal epithelium plays an important role in intestinal disease development. It not only establishes an important barrier against the gut lumen but also constantly signals information about the gut lumen and its composition to immune cells in the bowel wall. Such signaling across the epithelial barrier also occurs in the other direction. Intestinal epithelial cells respond to cytokines and other mediators of immune cells in the lamina propria and shape the microbial community within the gut by producing various antimicrobial peptides. Thus, the epithelium can be considered as an interpreter between the microbiota and the mucosal immune system, safeguarding and moderating communication to the benefit of the host. Type 2 immune responses play important roles in immune-epithelial communication. They contribute to gut tissue homeostasis and protect the host against infections with helminths. However, they are also involved in pathogenic pathways in inflammatory bowel disease and colorectal cancer. The current review provides an overview of current concepts regarding type 2 immune responses in intestinal physiology and pathophysiology.
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10
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Recent advances in inflammatory bowel disease therapy. Eur J Pharm Sci 2020; 155:105550. [DOI: 10.1016/j.ejps.2020.105550] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 07/29/2020] [Accepted: 09/11/2020] [Indexed: 02/06/2023]
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11
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Serological cytokine signature in paediatric patients with inflammatory bowel disease impacts diagnosis. Sci Rep 2020; 10:14638. [PMID: 32884009 PMCID: PMC7471680 DOI: 10.1038/s41598-020-71503-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 07/21/2020] [Indexed: 12/03/2022] Open
Abstract
Endoscopy is a central tool for diagnosing and evaluating paediatric inflammatory bowel diseases (PIBD), but is too invasive to be frequently repeated in young children. Furthermore, it is challenging to distinguish Crohn’s disease (CD) from ulcerative colitis (UC) endoscopically. This study aimed to determine biomarkers useful for the diagnosis of PIBD. Cytokines, chemokines, and growth factors were quantified in the sera of 15 patients with CD or UC, at disease onset prior to treatment, and 26 age-matched controls. Correlation of cytokine levels with the paediatric CD activity index (PCDAI) and the paediatric UC activity index (PUCAI) was analysed. Interleukin (IL)-6, IL-13, IL-7, and vascular endothelial growth factor were higher in the CD group than in the UC group. The receiver operating characteristic curve analysis showed that IL-7 was a putative biomarker for distinguishing CD from UC (area under the curve: 0.94). Granulocyte–macrophage colony-stimulating factor was associated with PCDAI, and an IL-1 receptor antagonist, IL-6, and macrophage inflammatory protein-1β were associated with PUCAI. These findings indicate significant differences in cytokine signatures among patients with new-onset PIBD, which may improve accuracy in diagnosing PIBD.
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12
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Cordes F, Foell D, Ding JN, Varga G, Bettenworth D. Differential regulation of JAK/STAT-signaling in patients with ulcerative colitis and Crohn’s disease. World J Gastroenterol 2020; 26:4055-4075. [PMID: 32821070 PMCID: PMC7403801 DOI: 10.3748/wjg.v26.i28.4055] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/24/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023] Open
Abstract
In 2018, the pan-Janus kinase (JAK) inhibitor tofacitinib was launched for the treatment of ulcerative colitis (UC). Although tofacitinib has proven efficacious in patients with active UC, it failed in patients with Crohn’s disease (CD). This finding strongly hints at a different contribution of JAK signaling in both entities. Here, we review the current knowledge on the interplay between the JAK/signal transducer and activator of transcription (STAT) pathway and inflammatory bowel diseases (IBD). In particular, we provide a detailed overview of the differences and similarities of JAK/STAT-signaling in UC and CD, highlight the impact of the JAK/STAT pathway in experimental colitis models and summarize the published evidence on JAK/STAT-signaling in immune cells of IBD as well as the genetic association between the JAK/STAT pathway and IBD. Finally, we describe novel treatment strategies targeting JAK/STAT inhibition in UC and CD and comment on the limitations and challenges of the new drug class.
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Affiliation(s)
- Friederike Cordes
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster D-48149, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster D-48149, Germany
| | - John Nik Ding
- Department of Gastroenterology, St. Vincent’s Hospital, Melbourne 3002, Australia
- Department of Medicine, University of Melbourne, East Melbourne 3002, Australia
| | - Georg Varga
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster D-48149, Germany
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster D-48149, Germany
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13
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Hsu CY, Fu SH, Chien MW, Liu YW, Chen SJ, Sytwu HK. Post-Translational Modifications of Transcription Factors Harnessing the Etiology and Pathophysiology in Colonic Diseases. Int J Mol Sci 2020; 21:ijms21093207. [PMID: 32369982 PMCID: PMC7246881 DOI: 10.3390/ijms21093207] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/23/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023] Open
Abstract
Defects in mucosal immune balance can lead to colonic diseases such as inflammatory bowel diseases and colorectal cancer. With the advancement of understanding for the immunological and molecular basis of colonic disease, therapies targeting transcription factors have become a potential approach for the treatment of colonic disease. To date, the biomedical significance of unique post-translational modifications on transcription factors has been identified, including phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, and O-GlcNAcylation. This review focuses on our current understanding and the emerging evidence of how post-translational regulations modify transcription factors involved in the etiology and pathophysiology of colonic disease as well as the implications of these findings for new therapeutic approaches in these disorders.
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Affiliation(s)
- Chao-Yuan Hsu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No.35, Keyan Road, Zhunan, Miaoli 350, Taiwan; (C.-Y.H.); (S.-H.F.)
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No.161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan; (M.-W.C.); (S.-J.C.)
| | - Shin-Huei Fu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No.35, Keyan Road, Zhunan, Miaoli 350, Taiwan; (C.-Y.H.); (S.-H.F.)
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No.161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan; (M.-W.C.); (S.-J.C.)
| | - Ming-Wei Chien
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No.161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan; (M.-W.C.); (S.-J.C.)
| | - Yu-Wen Liu
- Graduate Institute of Life Sciences, National Defense Medical Center, No.161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan;
- Molecular Cell Biology, Taiwan International Graduate Program, No.128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan
| | - Shyi-Jou Chen
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No.161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan; (M.-W.C.); (S.-J.C.)
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, No. 325, Section 2, Chenggong Rd., Neihu District, Taipei 114, Taiwan
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No.35, Keyan Road, Zhunan, Miaoli 350, Taiwan; (C.-Y.H.); (S.-H.F.)
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No.161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan; (M.-W.C.); (S.-J.C.)
- Graduate Institute of Life Sciences, National Defense Medical Center, No.161, Section 6, Min Chuan East Road, Neihu, Taipei 114, Taiwan;
- Correspondence: ; Tel.: +886-2-8792-3100 (ext. 18539); Fax: +886-2-8792-1774
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14
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Tindemans I, Joosse ME, Samsom JN. Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD. Cells 2020; 9:E110. [PMID: 31906479 PMCID: PMC7016883 DOI: 10.3390/cells9010110] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/20/2019] [Accepted: 12/26/2019] [Indexed: 12/12/2022] Open
Abstract
Infiltration of the lamina propria by inflammatory CD4+ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4+ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4+ T-cell populations is crucial to prevent uncontrolled CD4+ T-cell responses and subsequent intestinal tissue damage. While at steady state, T-cells display mainly a regulatory phenotype, increased in Th1, Th2, Th9, Th17, and Th17.1 responses, and reduced Treg and Tr1 responses have all been suggested to play a role in IBD pathophysiology. However, it is highly unlikely that all these responses are altered in each individual patient. With the rapidly expanding plethora of therapeutic options to inhibit inflammatory T-cell responses and stimulate regulatory T-cell responses, a crucial need is emerging for a robust set of immunological assays to predict and monitor therapeutic success at an individual level. Consequently, it is crucial to differentiate dominant inflammatory and regulatory CD4+ T helper responses in patients and relate these to disease course and therapy response. In this review, we provide an overview of how intestinal CD4+ T-cell responses arise, discuss the main phenotypes of CD4+ T helper responses, and review how they are implicated in IBD.
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Affiliation(s)
| | | | - Janneke N. Samsom
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus MC-Sophia Children’s Hospital, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
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15
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Scarozza P, Schmitt H, Monteleone G, Neurath MF, Atreya R. Oligonucleotides-A Novel Promising Therapeutic Option for IBD. Front Pharmacol 2019; 10:314. [PMID: 31068803 PMCID: PMC6491809 DOI: 10.3389/fphar.2019.00314] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 03/14/2019] [Indexed: 12/12/2022] Open
Abstract
Inflammatory Bowel Diseases (IBD), whose denomination comprehends Crohn's Disease (CD) and Ulcerative Colitis (UC), are intestinal chronic diseases that often require lifelong medical therapy. In the last two decades monoclonal antibodies against the cytokine TNF have become integral parts in the treatment of IBD patients, however there are unwanted side-effects and one third of patients show primary non-response while another subgroup loses response over time. Finding novel drugs which could act as therapies against precise pro-inflammatory molecular targets to avoid unwanted systemic side effects and additionally the process of immunization, represents an important aim for subsequent therapeutic approaches. Oligonucleotide based therapies represent a promising novel concept for the treatment of IBD. The molecular action of oligonucleotides ranges from inhibition of the translational process of mRNA transcripts of pro-inflammatory molecules, to mimicking bacterial DNA which can activate cellular targets for immunomodulation. Alicaforsen, selectively targets ICAM-1 mRNA. ICAM-1 is an adhesion molecule which is upregulated on endothelial cells during IBD, thereby mediating the adhesion and migration of leucocytes from blood to sites of active inflammation. In CD parenteral application of alicaforsen did not show therapeutic efficacy in phase II trials, but it demonstrated an improved efficacy as a topical enema in distal UC. Topical application of alicaforsen might represent a therapeutic perspective for refractory pouchitis as well. SMAD7 is a protein that inhibits the signaling of TGFβ, which is the mainstay of a regulatory counterpart in cellular immune responses. An antisense oligonucleotide against SMAD7 mRNA (mongersen) demonstrated pre-clinical and phase II efficacy in CD, but a phase III clinical trial was stopped due to lack of efficacy. Cobitolimod is a single strand oligonucleotide, which mimics bacterial DNA as its CpG dinucleotide sequences can be recognized by the Toll-like receptor 9 on different immune cells thereby causing induction of different cytokines, for example IL10 and IFNα. Topical application of cobitolimod was studied in UC patients. We will also discuss two other novel oligonucleotides which act on the GATA3 transcription factor (SB012) and on carbohydrate sulfotransferase 15 (STNM01), which could both represent novel promising therapeutic options for the treatment of UC.
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Affiliation(s)
- Patrizio Scarozza
- Department of Systems Medicine, Gastroenterology, University of Tor Vergata, Rome, Italy
- Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Heike Schmitt
- Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Giovanni Monteleone
- Department of Systems Medicine, Gastroenterology, University of Tor Vergata, Rome, Italy
| | - Markus F. Neurath
- Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
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16
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Hartmann AK, Cairns-Gibson DF, Santiana JJ, Tolentino MQ, Barber HM, Rouge JL. Enzymatically Ligated DNA-Surfactants: Unmasking Hydrophobically Modified DNA for Intracellular Gene Regulation. Chembiochem 2018; 19:1734-1739. [PMID: 29862626 DOI: 10.1002/cbic.201800302] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Indexed: 01/07/2023]
Abstract
Herein, we describe the characterization of a novel self-assembling and intracellular disassembling nanomaterial for nucleic acid delivery and targeted gene knockdown. By using a recently developed nucleic acid nanocapsule (NAN) formed from surfactants and conjugated DNAzyme (DNz) ligands, it is shown that DNz-NAN can enable cellular uptake of the DNAzyme and result in 60 % knockdown of a target gene without the use of transfection agents. The DNAzyme also exhibits activity without chemical modification, which we attribute to the underlying nanocapsule design and release of hydrophobically modified nucleic acids as a result of enzymatically triggered disassembly of the NAN. Fluorescence-based experiments indicate that the surfactant-conjugated DNAzymes are better able to access a fluorescent mRNA target within a mock lipid bilayer system than the free DNAzyme, highlighting the advantage of the hydrophobic surfactant modification to the nucleic acid ligands. In vitro characterization of DNz-NAN's substrate-cleavage kinetics, stability in biological serum, and persistence of knockdown against a proinflammatory transcription factor, GATA-3, are presented.
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Affiliation(s)
- Alyssa K Hartmann
- Department of Chemistry, University of Connecticut, Storrs, CT, 06269, USA
| | | | - Joshua J Santiana
- Department of Chemistry, University of Connecticut, Storrs, CT, 06269, USA
| | - Mark Q Tolentino
- Department of Chemistry, University of Connecticut, Storrs, CT, 06269, USA
| | - Halle M Barber
- Department of Chemistry, University of Connecticut, Storrs, CT, 06269, USA
| | - Jessica L Rouge
- Department of Chemistry, University of Connecticut, Storrs, CT, 06269, USA
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17
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Imam T, Park S, Kaplan MH, Olson MR. Effector T Helper Cell Subsets in Inflammatory Bowel Diseases. Front Immunol 2018; 9:1212. [PMID: 29910812 PMCID: PMC5992276 DOI: 10.3389/fimmu.2018.01212] [Citation(s) in RCA: 188] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/15/2018] [Indexed: 12/30/2022] Open
Abstract
The gastrointestinal tract is a site of high immune challenge, as it must maintain a delicate balance between tolerating luminal contents and generating an immune response toward pathogens. CD4+ T cells are key in mediating the host protective and homeostatic responses. Yet, CD4+ T cells are also known to be the main drivers of inflammatory bowel disease (IBD) when this balance is perturbed. Many subsets of CD4+ T cells have been identified as players in perpetuating chronic intestinal inflammation. Over the last few decades, understanding of how each subset of Th cells plays a role has dramatically increased. Simultaneously, this has allowed development of therapeutic innovation targeting specific molecules rather than broad immunosuppressive agents. Here, we review the emerging evidence of how each subset functions in promoting and sustaining the chronic inflammation that characterizes IBD.
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Affiliation(s)
- Tanbeena Imam
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sungtae Park
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
| | - Mark H Kaplan
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Matthew R Olson
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States.,Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
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18
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Interleukin-4 and interleukin-13 increase NADPH oxidase 1-related proliferation of human colon cancer cells. Oncotarget 2018; 8:38113-38135. [PMID: 28498822 PMCID: PMC5503519 DOI: 10.18632/oncotarget.17494] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 04/17/2017] [Indexed: 01/01/2023] Open
Abstract
Human colon cancers express higher levels of NADPH oxidase 1 [NOX1] than adjacent normal epithelium. It has been suggested that reactive oxygen species [ROS] derived from NOX1 contribute to DNA damage and neoplastic transformation in the colon, particularly during chronic inflammatory stress. However, the mechanism(s) underlying increased NOX1 expression in malignant tumors or chronic inflammatory states involving the intestine are poorly characterized. We examined the effects of two pro-inflammatory cytokines, IL-4 and IL-13, on the regulation of NOX1. NOX1 expression was increased 4- to 5-fold in a time- and concentration-dependent manner by both cytokines in human colon cancer cell lines when a functional Type II IL-4 receptor was present. Increased NOX1 transcription following IL-4/IL-13 exposure was mediated by JAK1/STAT6 signaling, was associated with a ROS-related inhibition of protein tyrosine phosphatase activity, and was dependent upon activation and specific binding of GATA3 to the NOX1 promoter. NOX1-mediated ROS production increased cell cycle progression through S-phase leading to a significant increase in cellular proliferation. Evaluation of twenty pairs of surgically-resected colon cancers and their associated uninvolved adjacent colonic epithelium demonstrated a significant increase in the active form of NOX1, NOX1-L, in tumors compared to normal tissues, and a significant correlation between the expression levels of NOX1 and the Type II IL-4 receptor in tumor and the uninvolved colon. These studies imply that NOX1 expression, mediated by IL-4/IL-13, could contribute to an oxidant milieu capable of supporting the initiation or progression of colonic cancer, suggesting a role for NOX1 as a therapeutic target.
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Li J, Yan Y, Meng Z, Liu S, Beck PL, Ghosh S, Qian J, Gui X. Microscopic Colitis Evolved Into Inflammatory Bowel Diseases Is Characterized by Increased Th1/Tc1 Cells in Colonic Mucosal Lamina Propria. Dig Dis Sci 2017; 62:2755-2767. [PMID: 28597107 DOI: 10.1007/s10620-017-4636-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 05/26/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND An association between microscopic colitis (MC), i.e., lymphocytic colitis (LC) and collagenous colitis (CC), and inflammatory bowel diseases (IBD) has been noticed. A subset of MC cases may evolve into IBD, and IBD in remission may present as MC in a histologic pattern. Moreover, MC and IBD may coexist in different regions of the bowel. A link between MC and IBD in their pathogenesis is, therefore, suggested. Abnormal mucosal immunity is likely the key. METHODS We reviewed 2324 MC cases in Calgary over 14 years and identified 20 cases evolved into IBD (IBD transformers). 13 of them were further investigated for colonic mucosal lamina propria mononuclear cells (LPMNCs), as opposed to 22 cases whose MC resolved. On their index colonic biopsy immunohistochemistry was performed to detect major T cell subsets characterized by key cytokines and master transcription factors (IFNγ and T-bet for Th1/Tc1, GATA-3 for Th2/Tc2, IL-17 and RORc for Th17/Tc17, FoxP3 for Treg/Tcreg) as well as TNFα+ cells (partly representing Th1). LPMNCs positive for each marker were counted (average number per high-power field). RESULTS IBD transformers had increased IFNγ+, T-bet+, TNF-α+, and GATA-3+ LPMNCs compared to the MC-resolved cases. The LC-to-IBD subgroup had increased IFNγ+ and GATA-3+ cells compared to the LC-resolved subgroup. The CC-to-IBD subgroup had increased T-bet+, TNF-α+, and GATA-3+ cells compared to the CC-resolved subgroup. Among MC-resolved patients, more TNF-α+ and RORc+ cells were seen in LC than in CC. CONCLUSION Th1/Tc1- and TNFα-producing cells, and likely a subset of Th2/Tc2 cells as well, may be involved in the MC-to-IBD transformation.
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Affiliation(s)
- Ji Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
- Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, AB, Canada
| | - Yuchu Yan
- Calgary Laboratory Services, Calgary, AB, Canada
| | - Ziran Meng
- Calgary Laboratory Services, Calgary, AB, Canada
| | - Shuhong Liu
- Calgary Laboratory Services, Calgary, AB, Canada
| | - Paul L Beck
- Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, AB, Canada
| | - Subrata Ghosh
- Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, AB, Canada
- Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
| | - Xianyong Gui
- Calgary Laboratory Services, Calgary, AB, Canada.
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
- Department of Pathology, Foothills Medical Centre, 1403 29 Street NW, Calgary, AB, T2N 2T9, Canada.
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20
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Dai S, Gu H, Lin Q, Xing T, Chen M, Zhong T, Wu G, Feng Y, Liu H, Gao Y, Jian H, Zhang M, Mo H, Zhu H, Chen D, Xu J, Zou Y, Chi H, Zhu Y. Disequilibrium in the CD8 +CD28 +/CD8 +CD28 - T Lymphocyte Balance Is Related to Prognosis in Rats with Trinitrobenzenesulfonic Acid-Induced Colitis. Dig Dis Sci 2017; 62:639-651. [PMID: 28035546 DOI: 10.1007/s10620-016-4424-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 12/16/2016] [Indexed: 12/18/2022]
Abstract
PURPOSE The CD8+CD28+/CD8+CD28- T lymphocyte balance is vital for human ulcerative colitis (UC) but has not been defined in experimental colitis. This investigation will try to identify the changes that occur in the CD8+CD28+/CD8+CD28- T lymphocyte balance during the progression of trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. METHODS The frequencies of blood CD8+CD28+ and CD8+CD28- T lymphocytes were detected in the rats belonging to the normal, model, and treated groups on five days using flow cytometry. The treated rats were administered with mesalazine and were euthanized after a 14-day treatment, as were the normal and model rats. The sensitivity and specificity of the CD8+CD28+/CD8+CD28- T lymphocyte balance in diagnosing early colitis were analyzed by receiver operating characteristics (ROC) curves. The frequencies of CD8+CD28+ and CD8+CD28- T lymphocytes in the colon tissue were tested via immunofluorescence. ELISA was used to measure the levels of the cytokines. Immunohistochemistry and Western blotting were used to detect the colonic expression of JAK3, STAT6, NFATc2, and GATA3. RESULTS We found that the ratio of CD8+CD28+/CD8+CD28- T lymphocytes decreased, as did the level of interleukin-7, but not IL-12p40, IL-13, or IL-15, in the blood; however, the ratio increased along with JAK3, STAT6, NFATc2, and GATA3 in the colon of the rats with colitis. The changes were effectively reversed through the administration of mesalazine for 13 days. Surprisingly, the balance in the blood could sensitively distinguish rats with early colitis from normal rats. CONCLUSION These data show that increase in CD8+CD28+ T cells in blood and decrease in CD8+CD28- T cells in colon are associated with experimental colitis.
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Affiliation(s)
- Shixue Dai
- Department of Rheumatology, TCM-Integrated Hospital, Southern Medical University, No. 13, Shiliugang Road, Haizhu District, Guangzhou, 510315, Guangdong, People's Republic of China.
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China.
- Department of Gastroenterology, Guangdong General Hospital and Guangdong Academy of Medical Sciences, South China University of Technology, Guangzhou, 510080, People's Republic of China.
| | - Hongxiang Gu
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Qianyi Lin
- Undergraduate of Grade 2013, The First Clinical College, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Tiaosi Xing
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA
| | - Minhua Chen
- Undergraduate of Grade 2013, School of Public Health, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Tao Zhong
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Gang Wu
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Yanling Feng
- Department of Gastroenterology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, 223001, Jiangsu, People's Republic of China
| | - Hongbo Liu
- Department of Spleen and Stomach Diseases, Tai'an Hospital of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Tai'an, 271000, Shandong, People's Republic of China
| | - Yong Gao
- Department of Thoracic Surgery, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, 510900, Guangdong, People's Republic of China
| | - Hongjian Jian
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Minhai Zhang
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Hongmei Mo
- Department of Traditional Chinese Medicine, The Second Clinical Medical College, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Huanjie Zhu
- Department of Traditional Chinese Medicine, The Second Clinical Medical College, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Dongsheng Chen
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Jun Xu
- Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Ying Zou
- Department of Traditional Chinese Medicine, The Second Clinical Medical College, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Honggang Chi
- Department of Traditional Chinese Medicine, The Second Clinical Medical College, Guangdong Medical University, Dongguan, 523808, Guangdong, People's Republic of China
| | - Yuzhen Zhu
- Guangdong Key Laboratory for Research and Development of Natural Drug, Research Institute of Traditional Chinese Medicine, Guangdong Medical University, Zhanjiang, 524023, Guangdong, People's Republic of China
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21
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Popp V, Gerlach K, Mott S, Turowska A, Garn H, Atreya R, Lehr HA, Ho IC, Renz H, Weigmann B, Neurath MF. Rectal Delivery of a DNAzyme That Specifically Blocks the Transcription Factor GATA3 and Reduces Colitis in Mice. Gastroenterology 2017; 152:176-192.e5. [PMID: 27639807 DOI: 10.1053/j.gastro.2016.09.005] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 09/01/2016] [Accepted: 09/06/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS GATA3 is a transcription factor that regulates T-cell production of cytokines. We investigated the role of GATA3 in development of colitis in mice. METHODS We performed quantitative polymerase chain reaction and immunofluorescence analyses of colon tissues from patients with Crohn's disease (n = 61) or ulcerative colitis (UC, n = 74) or from patients without inflammatory bowel diseases (n = 22), to measure levels of GATA3. Colitis was induced by administration of oxazolone or 2,4,6-trinitrobenzenesulfonic acid to control mice, mice with T-cell-specific deletion of GATA3, and mice with deletion of tumor necrosis factor receptor (TNFR) 1 and TNFR2 (TNFR double knockouts); some mice were given a GATA3-specific DNAzyme (hgd40) or a control DNAzyme via intrarectal administration, or systemic injections of an antibody to TNF before or during sensitization and challenge phase of colitis induction. Colon tissues were collected and immunofluorescence and histochemical analyses were performed. Lamina propria mononuclear cells and T cells were isolated and analyzed by flow cytometry or cytokine assays. Colonic distribution of labeled DNAzyme and inflammation were monitored by in vivo imaging (endoscopy) of mice. RESULTS Levels of GATA3 messenger RNA were higher in colon tissues from patients with UC, but not ileal Crohn's disease, than control tissues; levels of GATA3 correlated with levels of inflammatory cytokines (interleukin [IL] 9, IL17A, IL6, IL5, IL4, IL13, and TNF). We observed increased expression of GATA3 by lamina propria T cells from mice with colitis compared with controls. Mice with T-cell-specific deletion of GATA3 did not develop colitis and their colonic tissues did not produce inflammatory cytokines (IL6, IL9, or IL13). The DNAzyme hgd40 inhibited expression of GATA3 messenger RNA by unstimulated and stimulated T cells, and distributed throughout the inflamed colons of mice with colitis. Colon tissues from mice given hgd40 had reduced expression of GATA3 messenger RNA, compared with mice given a control DNAzyme. Mice given hgd40 did not develop colitis after administration of oxazolone or 2,4,6-trinitrobenzenesulfonic acid; lamina propria cells from these mice expressed lower levels of IL6, IL9, and IL13 than cells from mice given the control DNAzyme. Mini-endoscopic images revealed that hgd40 and anti-TNF reduced colon inflammation over 3 days; hgd40 reduced colitis in TNFR double-knockout mice. CONCLUSIONS Levels of GATA3 are increased in patients with UC and correlate with production of inflammatory cytokines in mice and humans. A DNAzyme that prevents expression of GATA3 reduces colitis in mice, independently of TNF, and reduces levels of cytokines in the colon. This DNAzyme might be developed for treatment of patients with UC.
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Affiliation(s)
- Vanessa Popp
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany
| | - Katharina Gerlach
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany
| | - Stefanie Mott
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany
| | | | - Holger Garn
- Institute of Laboratory Medicine and Pathobiochemistry, Medical Faculty, Philipps University of Marburg, Marburg, Germany
| | - Raja Atreya
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany
| | - Hans-Anton Lehr
- Institute of Pathology, Campus Bodensee, Friedrichshafen, Germany
| | - I-Cheng Ho
- Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts
| | - Harald Renz
- Institute of Laboratory Medicine and Pathobiochemistry, Medical Faculty, Philipps University of Marburg, Marburg, Germany
| | - Benno Weigmann
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany.
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22
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Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res 2016; 176:38-68. [PMID: 27220087 DOI: 10.1016/j.trsl.2016.04.009] [Citation(s) in RCA: 129] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 03/17/2016] [Accepted: 04/28/2016] [Indexed: 12/14/2022]
Abstract
Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored. These include various gut proteins (CXCL-10, GATA-3, NKG2D, CD98, microRNAs), immune cells recruited to the gut (mast cells, eosinophils, toll-like receptors 2, 4), dysregulated proinflammatory cytokines (interleukin-6, -13, -18, -21), and commensal microbiota (probiotics and fecal microbiota transplantation). We also evaluate some of the emerging nonconventional therapies being explored in IBD treatment focusing on the latest developments in stem cell research, oral targeting of the gut-associated lymphoid tissue, novel anti-inflammatory signaling pathway targeting, adenosine deaminase inhibition, and the beneficial effects of antioxidant and nutraceutical therapies. In addition, we highlight the growth of biologics and their targets in IBD by providing information on the preclinical and clinical development of over 60 biopharmaceuticals representing the state of the art in ulcerative colitis and Crohn's disease drug development.
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Abstract
To date, we encounter more and more pediatric patients with ulcerative colitis (UC). For yet unclear reasons, UC in pediatric patients seems to be a more aggressive and extensive disease than in their adult counterparts. In the majority of pediatric patients, the disease presents as pancolitis. The severity of the disease is reflected in the high use of corticosteroids and immunosuppressants and a high rate of surgery for medically refractory patients. The means by which to assess disease activity or to accurately predict its course are far from optimal. This review summarizes the current knowledge on the means for assessing UC activity in children. Research for developing new tools by which to monitor and forecast disease activity, are needed in all areas including invasive endoscopy, clinical evaluation, and treatment follow-up.
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Affiliation(s)
- Kaija-Leena Kolho
- a Children's Hospital , Helsinki University Central Hospital, University of Helsinki , Helsinki , Finland
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Nicol L, Wilkie H, Gossner A, Watkins C, Dalziel R, Hopkins J. Variations in T cell transcription factor gene structure and expression associated with the two disease forms of sheep paratuberculosis. Vet Res 2016; 47:83. [PMID: 27530627 PMCID: PMC4988036 DOI: 10.1186/s13567-016-0368-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 07/27/2016] [Indexed: 12/24/2022] Open
Abstract
Two different forms of clinical paratuberculosis in sheep are recognised, related to the level of bacterial colonization. Paucibacillary lesions are largely composed of lymphocytes with few bacteria, and multibacillary pathology is characterized by heavily-infected macrophages. Analysis of cytokine transcripts has shown that inflammatory Th1/Th17 T cells are associated with development of paucibacillary pathology and Th2 cytokines are correlated with multibacillary disease. The master regulator T cell transcription factors TBX21, GATA3, RORC2 and RORA are critical for the development of these T cell subsets. Sequence variations of the transcription factors have also been implicated in the distinct disease forms of human mycobacterial and gastrointestinal inflammatory diseases. Relative RT-qPCR was used to compare expression levels of each transcript variant of the master regulators in the ileo-caecal lymph nodes of uninfected controls and sheep with defined paucibacillary and multibacillary pathology. Low levels of GATA3 in multibacillary sheep failed to confirm that multibacillary paratuberculosis is caused simply by a Th2 immune response. However, high levels of TBX21, RORC2 and RORC2v1 highlights the role of Th1 and Th17 activation in paucibacillary disease. Increased RORAv1 levels in paucibacillary tissue suggests a role for RORα in Th17 development in sheep; while elevated levels of RORAv4 hints that this variant might inhibit RORα function and depress Th17 development in multibacillary sheep.
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Affiliation(s)
- Louise Nicol
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Hazel Wilkie
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Anton Gossner
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Craig Watkins
- Moredun Research Institute, International Research Centre, Pentlands Science Park, Penicuik, Midlothian, EH26 0PZ, UK
| | - Robert Dalziel
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - John Hopkins
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.
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Profiles of Lamina Propria T Helper Cell Subsets Discriminate Between Ulcerative Colitis and Crohn's Disease. Inflamm Bowel Dis 2016; 22:1779-92. [PMID: 27243594 DOI: 10.1097/mib.0000000000000811] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Distinction between 2 forms of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), can be challenging. Aberrant mucosal immunity suggests that CD is a T helper type 1 cell (Th1)-driven disease, whereas UC as Th2-driven response. However, whether this paradigm truly distinguishes CD from UC is controversial. We aimed to clarify the discriminating potential of lamina propria Th subsets in patients with IBD. METHODS Biopsies from 79 patients with IBD and 20 healthy controls were collected for Th subsets analysis (Th1:interferon γ [IFN-γ], T-bet; Th2:interleukin 13 [IL-13], Gata3; Th17:IL-17, RORγt; Treg:FoxP3). The receiver-operating characteristic curves were constructed to assess the discriminating ability by calculating the area under the receiver-operating characteristic curve. The equation with the highest area under the receiver-operating characteristic curve was applied to newly diagnosed patients to evaluate discriminating ability. RESULTS Patients with CD showed increased IFN-γ or T-bet cells and decreased IL-13 or Gata3 cells compared with UC. A discriminant equation composed of 4 markers (IFN-γ, T-bet, IL-13, and Gata3) yielded the highest area under the receiver-operating characteristic curve. In 36 established CD or UC, the sensitivity, specificity, positive and negative predictive probabilities were 92.6%, 55.6%, 86.2%, and 71.4% and in 14 newly diagnosed patients were 100.0%, 42.9%, 63.6%, and 100.0%. Furthermore, Gata3 cells were increased in tumor necrosis factor inhibitor therapy nonresponders compared with responders in CD. IFN-γ cells were directly and inversely proportional to disease activity in patients with CD and UC, respectively. CONCLUSIONS The Th1/Th2 paradigm can distinguish CD from UC and may be further associated with response to tumor necrosis factor inhibitor in CD and disease activity in patients with IBD.
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Izzo R, Bevivino G, Monteleone G. Tofacitinib for the treatment of ulcerative colitis. Expert Opin Investig Drugs 2016; 25:991-7. [PMID: 27177233 DOI: 10.1080/13543784.2016.1189900] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Management of patients with active ulcerative colitis (UC), one of the most frequent inflammatory bowel diseases in human beings, is mainly based on the use of mesalamine and corticosteroids. Since in the long-term, these two drugs may be ineffective in nearly one third of the patients, immunosuppressants and/or biologics are needed to control disease activity. AREAS COVERED The marked activation of JAK/STAT molecules in inflamed mucosa of UC patients and the demonstration that UC-associated mucosal injury is driven by soluble factors that signal through JAK/STAT pathways led to investigation of JAK inhibitors for the treatment of active UC. Tofacitinib, an oral inhibitor of the cytokine-driven JAK-STAT signalling cascade, has recently been proposed for the treatment of moderate-to-severe UC. Phase 2 study showed the efficacy of tofacitinib to induce clinical and endoscopic improvement/remission and the safety profile of the drug. Herein the authors review this compound. EXPERT OPINION The results obtained from clinical trials with tofacitinib suggest that this drug could be a new treatment option for patients with moderate to severe UC. However, further experimentation is needed to assess the efficacy of this drug in selected subgroups of patients as well as to maintain remission and to determine the long-term safety profile of the drug.
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Affiliation(s)
- Roberta Izzo
- a Department of Systems Medicine , University of Rome 'Tor Vergata' , Rome , Italy
| | - Gerolamo Bevivino
- a Department of Systems Medicine , University of Rome 'Tor Vergata' , Rome , Italy
| | - Giovanni Monteleone
- a Department of Systems Medicine , University of Rome 'Tor Vergata' , Rome , Italy
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Hisamatsu T, Erben U, Kühl AA. The Role of T-Cell Subsets in Chronic Inflammation in Celiac Disease and Inflammatory Bowel Disease Patients: More Common Mechanisms or More Differences? Inflamm Intest Dis 2016; 1:52-62. [PMID: 29922658 DOI: 10.1159/000445133] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 03/02/2016] [Indexed: 12/13/2022] Open
Abstract
Background Chronic intestinal inflammation due to noninfectious causes represents a growing health issue all over the world. Celiac disease as well as inflammatory bowel diseases (IBD) like Crohn's disease and ulcerative and microscopic colitis involve uncontrolled T-cell activation and T-cell-mediated damage as common denominators. Therefore, diagnosis and treatment decisions clearly benefit from the knowledge of the intricacies of the systemic and the local T-cell activity. Summary Depending on the cytokine milieu, CD4+ T cells can differentiate into proinflammatory T helper 1 (Th1), anti-inflammatory Th2, antimicrobial Th17, pleiotropic Th9, tissue-instructing Th22 cells, and in the regulatory compartment forkhead box protein 3+ Treg, suppressive Tr1 or Th3 cells. Additionally, follicular Th cells provide B-cell help in antibody class switching; cytotoxic CD8+ T cells target virus-infected or tumor cells. This review discusses our current knowledge on the contribution of defined T-cell subpopulations to establishing and maintaining chronic intestinal inflammation in either of the above entities. It also puts emphasis on the differences in the prevalence of these diseases between Eastern and Western countries. Key Messages In celiac disease, the driving role of T cells in the lamina propria and in the epithelium mainly specific for two defined antigens is well established. Differences in genetics and lifestyle between Western and Eastern countries were instrumental in understanding underlying mechanisms. In IBD, the vast amount of potential antigens and the corresponding antigen-specific T cells makes it unlikely to find universal triggers. Increased mucosal CD4+ regulatory T cells in all four entities fail to control or abrogate local inflammatory processes. Thus, prevailing differences in the functional T-cell subtypes driving chronic intestinal inflammation in celiac disease and IBD at best allow some overlap in the treatment options for either disease.
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Affiliation(s)
- Tadakazu Hisamatsu
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
| | - Ulrike Erben
- Medical Department (Gastroenterology/Infectious Diseases/Rheumatology), Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Research Center ImmunoSciences, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Anja A Kühl
- Medical Department (Gastroenterology/Infectious Diseases/Rheumatology), Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Research Center ImmunoSciences, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Integrating Immunologic Signaling Networks: The JAK/STAT Pathway in Colitis and Colitis-Associated Cancer. Vaccines (Basel) 2016; 4:vaccines4010005. [PMID: 26938566 PMCID: PMC4810057 DOI: 10.3390/vaccines4010005] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 02/19/2016] [Accepted: 02/25/2016] [Indexed: 12/12/2022] Open
Abstract
Cytokines are believed to be crucial mediators of chronic intestinal inflammation in inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). Many of these cytokines trigger cellular effects and functions through signaling via janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules. In this way, JAK/STAT signaling controls important events like cell differentiation, secretion of cytokines or proliferation and apoptosis in IBD in both adaptive and innate immune cells. Moreover, JAK/STAT signaling, especially via the IL-6/STAT3 axis, is believed to be involved in the transition of inflammatory lesions to tumors leading to colitis-associated cancer (CAC). In this review, we will introduce the main cellular players and cytokines that contribute to pathogenesis of IBD by JAK/STAT signaling, and will highlight the integrative function that JAK/STATs exert in this context as well as their divergent role in different cells and processes. Moreover, we will explain current concepts of the implication of JAK/STAT signaling in CAC and finally discuss present and future therapies for IBD that interfere with JAK/STAT signaling.
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Wilkie H, Gossner A, Bishop S, Hopkins J. Variations in T Cell Transcription Factor Sequence and Expression Associated with Resistance to the Sheep Nematode Teladorsagia circumcincta. PLoS One 2016; 11:e0149644. [PMID: 26890074 PMCID: PMC4759366 DOI: 10.1371/journal.pone.0149644] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 02/03/2016] [Indexed: 12/24/2022] Open
Abstract
This study used selected lambs that varied in their resistance to the gastrointestinal parasite Teladorsagia circumcincta. Infection over 12 weeks identified susceptible (high adult worm count, AWC; high fecal egg count, FEC; low body weight, BW; low IgA) and resistant sheep (no/low AWC and FEC, high BW and high IgA). Resistance is mediated largely by a Th2 response and IgA and IgE antibodies, and is a heritable characteristic. The polarization of T cells and the development of appropriate immune responses is controlled by the master regulators, T-bet (TBX21), GATA-3 (GATA3), RORγt (RORC2) and RORα (RORA); and several inflammatory diseases of humans and mice are associated with allelic or transcript variants of these transcription factors. This study tested the hypothesis that resistance of sheep to T. circumcincta is associated with variations in the structure, sequence or expression levels of individual master regulator transcripts. We have identified and sequenced one variant of sheep TBX21, two variants of GATA3 and RORC2 and five variants of RORA from lymph node mRNA. Relative RT-qPCR analysis showed that TBX21, GATA3 and RORC2 were not significantly differentially-expressed between the nine most resistant (AWC, 0; FEC, 0) and the nine most susceptible sheep (AWC, mean 6078; FEC, mean 350). Absolute RT-qPCR on all 45 animals identified RORVv5 as being significantly differentially-expressed (p = 0.038) between resistant, intermediate and susceptible groups; RORCv2 was not differentially-expressed (p = 0.77). Spearman’s rank analysis showed that RORAv5 transcript copy number was significantly negatively correlated with parameters of susceptibility, AWC and FEC; and was positively correlated with BW. RORCv2 was not correlated with AWC, FEC or BW but was significantly negatively correlated with IgA antibody levels. This study identifies the full length RORA variant (RORAv5) as important in controlling the protective immune response to T. circumcincta infection in sheep.
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Affiliation(s)
- Hazel Wilkie
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, United Kingdom
| | - Anton Gossner
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, United Kingdom
| | - Stephen Bishop
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, United Kingdom
| | - John Hopkins
- The Roslin Institute & R(D)SVS, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, United Kingdom
- * E-mail:
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Abstract
BACKGROUND Crohn's disease (CD) and ulcerative colitis (UC) are the major forms of inflammatory bowel disease, and pathogenesis involves a complex interplay among genetic, environmental, and immunological factors. We evaluated isoform expression of the IL-12-activated transcription factor STAT4 in children with CD and UC. METHODS We collected biopsy samples from both patients newly diagnosed with CD and with UC. We further collected blood samples from patients newly diagnosed with CD and with UC as well as from patients who had a flare-up after being in clinical remission, and we examined the ratios of STAT4β/STAT4α mRNA. In addition to STAT4 isoforms, we measured the expression of the cytokines TNFα, IFNγ, granulocyte macrophage-colony stimulating factor, and IL-17 using polymerase chain reaction of biopsy samples and multiplex analysis of patient serum samples. RESULTS Ratios of STAT4β/STAT4α were increased in specific gastrointestinal tract segments in both patients with CD and those with UC that correlate with the location and severity of inflammation. In contrast, we did not observe changes in STAT4β/STAT4α ratios in biopsy specimens from patients with eosinophilic esophagitis. We also observed increased STAT4β/STAT4α ratios in the peripheral blood mononuclear cells of patients with UC and those with CD, compared with healthy controls. Ratios were normalized after patients were treated with steroids. CONCLUSIONS Collectively, these data indicate that STAT4 isoforms could be an important noninvasive biomarker in the diagnosis and treatment of inflammatory bowel disease and that expression of these isoforms might provide further insight into the pathogenesis of IBD.
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Korolkova OY, Myers JN, Pellom ST, Wang L, M'Koma AE. Characterization of Serum Cytokine Profile in Predominantly Colonic Inflammatory Bowel Disease to Delineate Ulcerative and Crohn's Colitides. CLINICAL MEDICINE INSIGHTS. GASTROENTEROLOGY 2015; 8:29-44. [PMID: 26078592 PMCID: PMC4459555 DOI: 10.4137/cgast.s20612] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 11/23/2014] [Accepted: 11/23/2014] [Indexed: 02/05/2023]
Abstract
BACKGROUND As accessible diagnostic approaches fail to differentiate between ulcerative colitis (UC) and Crohn’s colitis (CC) in one-third of patients with predominantly colonic inflammatory bowel disease (IBD), leading to inappropriate therapy, we aim to investigate the serum cytokine levels in these patients in search of molecular biometric markers delineating UC from CC. METHODS We measured 38 cytokines, chemokines, and growth factors using magnetic-bead-based multiplex immunoassay in 25 UC patients, 28 CC patients, and 30 controls. Our results are compared with those from a review of current literature regarding advances in serum cytokine profiles and associated challenges preventing their use for diagnostic/prognostic purposes. RESULTS Univariate analysis showed statistically significant increases of eotaxin, GRO, and TNF-α in UC patients compared to controls (Ctrl); interferon γ, interleukin (IL)-6, and IL-7 in CC group compared to Ctrl; and IL-8 in both UC and CC versus Ctrl. No cytokines were found to be different between UC and CC. A generalized linear model identified combinations of cytokines, allowing the identification of UC and CC patients, with area under the curve (AUC) = 0.936, as determined with receiver operating characteristic (ROC) analysis. CONCLUSIONS The current knowledge available about circulating cytokines in IBD is often contradictory. The development of an evidence-based tool using cytokines for diagnostic accuracy is still preliminary.
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Affiliation(s)
- Olga Y Korolkova
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Jeremy N Myers
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Samuel T Pellom
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Li Wang
- Department of Statistics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Amosy E M'Koma
- Laboratory of Inflammatory Bowel Disease Research, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee. ; Department of General Surgery, Colon and Rectal Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee. ; Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
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Yu FY, Huang SG, Zhang HY, Ye H, Chi HG, Zou Y, Lv RX, Zheng XB. Effects of baicalin in CD4 + CD29 + T cell subsets of ulcerative colitis patients. World J Gastroenterol 2014; 20:15299-309. [PMID: 25386078 PMCID: PMC4223263 DOI: 10.3748/wjg.v20.i41.15299] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 06/08/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the role of baicalin in ulcerative colitis (UC) with regard to the CD4(+)CD29(+) T helper cell, its surface markers and serum inflammatory cytokines. METHODS Flow cytometry was used to detect the percentage of CD4(+)CD29(+) cells in patients with UC. Real time polymerase chain reaction was used to detect expression of GATA-3, forkhead box P3, T-box expressed in T cells (T-bet), and retinoic acid-related orphan nuclear hormone receptor C (RORC). Western blotting was used to analyze expression of nuclear factor-κB (NF-κB) p65, phosphorylation of NF-κB (p-NF-κB) p65, STAT4, p-STAT4, STAT6 and p-STAT6. The concentrations of interferon-γ (IFN-γ), interleukin (IL)-4, IL-5, IL-6, IL-10 and TGF-β in serum were determined by ELISA assay. RESULTS The percentages of CD4(+)CD29(+) T cells were lower in treatment with 40 and 20 μmol/L baicalin than in the treatment of no baicalin. Treatment with 40 or 20 μmol/L baicalin significantly upregulated expression of IL-4, TGF-β1 and IL-10, increased p-STAT6/STAT6 ratio, but downregulated expression of IFN-γ, IL-5, IL-6, RORC, Foxp3 and T-bet, and decreased ratios of T-bet/GATA-3, p-STAT4/STAT4 and p-NF-κB/NF-κB compared to the treatment of no baicalin. CONCLUSION The results indicate that baicalin regulates immune balance and relieves the ulcerative colitis-induced inflammation reaction by promoting proliferation of CD4(+)CD29(+) cells and modulating immunosuppressive pathways.
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Suratanee A, Plaimas K. Identification of inflammatory bowel disease-related proteins using a reverse k-nearest neighbor search. J Bioinform Comput Biol 2014; 12:1450017. [DOI: 10.1142/s0219720014500176] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic disease whose incidence and prevalence increase every year; however, the pathogenesis of IBD is still unclear. Thus, identifying IBD-related proteins is important for understanding its complex disease mechanism. Here, we propose a new and simple network-based approach using a reverse k-nearest neighbor ( R k NN ) search to identify novel IBD-related proteins. Protein–protein interactions (PPI) and Genome-Wide Association Studies (GWAS) were used in this study. After constructing the PPI network, the R k NN search was applied to all of the proteins to identify sets of influenced proteins among their k-nearest neighbors ( R k NNs ). An observed protein whose influenced proteins were mostly known IBD-related proteins was statistically identified as a novel IBD-related protein. Our method outperformed a random aspect, k NN search, and centrality measures based on the network topology. A total of 39 proteins were identified as IBD-related proteins. Of these proteins, 71% were reported at least once in the literature as related to IBD. Additionally, these proteins were found over-represented in the IBD pathway and enriched in importantly functional pathways in IBD. In conclusion, the R k NN search with the statistical enrichment test is a great tool to identify IBD-related proteins to better understand its complex disease mechanism.
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Affiliation(s)
- Apichat Suratanee
- Department of Mathematics, Faculty of Applied Science, King Mongkut's University of Technology North Bangkok, 1518 Pracharat 1 Road, Wongsawang, Bangsue, Bangkok 10800, Thailand
| | - Kitiporn Plaimas
- Integrative Bioinformatics and Systems Biology Group, Advanced Virtual and Intelligent Computing Research Center (AVIC), Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Phyathai Road, Patumwan, Bangkok 10330, Thailand
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Abstract
INTRODUCTION STAT4, which acts as the major signaling transducing STATs in response to IL-12, is a central mediator in generating inflammation during protective immune responses and immune-mediated diseases. AREAS COVERED This review summarizes that STAT4 is essential for the differentiation and function of a wide variety of immune cells, including natural killer cells, mast cells, dendritic cells and T helper cells. In addition, STAT4-mediated signaling promoted the production of autoimmune-associated components, which are implicated in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and psoriasis. EXPERT OPINION Due to its crucial roles in inflammation and autoimmunity, STAT4 may have promise as an effective therapeutic target for autoimmune diseases. Understanding the molecular mechanisms driving STAT4, together with knowledge on the ability of current immunosuppressive treatment to target this process, may open an avenue to novel therapeutic options.
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Affiliation(s)
- Yan Liang
- Anhui Medical University, School of Public Health, Department of Epidemiology and Biostatistics , Anhui, PR China
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Fujitake Y, Ohtsuka Y, Ikuse T, Ohtani K, Aoyagi Y, Fujii T, Kudo T, Ishii M, Shimizu T. Analysis of inflammatory signals in Japanese children with Crohn's disease. Pediatr Int 2013; 55:753-6. [PMID: 23773416 DOI: 10.1111/ped.12159] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2012] [Revised: 04/02/2013] [Accepted: 05/24/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND Although it is recognized that the Th1 and Th17 cytokines are directly involved in the pathogenesis of Crohn's disease (CD), the precise cause of pediatric CD in the Japanese population has not been well established. In the present study, we examined the expression of pro-inflammatory cytokines and their signaling molecules in the intestinal mucosa of Japanese children with acute- and remission-phase CD. METHODS A total of 11 children with acute-phase CD (mean age 10.32 ± 6.02 years) and 20 children with remission-phase CD (mean age 11.87 ± 4.29 years) provided samples for a serum cytokine assay. Among these children, seven with acute-phase CD (mean age 13.63 ± 1.94 years), six with remission-phase CD (mean age 9.93 ± 4.33 years), and six healthy controls (mean age 9.90 ± 4.88 years) provided samples for a signaling assay. Among this group, the expression of Th1, Th2, Th17, and regulatory T-cell signaling molecules were examined by real-time polymerase chain reaction. RESULTS A significant elevation in the serum level of interleukin-6 and tumor necrosis factor-α was confirmed in pediatric patients with acute-phase CD compared to patients with remission-phase CD (P < 0.01 and 0.05, respectively). The mucosal expression of interferon-γ, signal transducer and activator of transcription 4, and transforming growth factor-β1 were significantly enhanced in pediatric patients with acute-phase CD compared to patients with remission-phase CD or those with normal mucosa. CONCLUSIONS These results suggest the possible involvement of Th1 and Th17 signaling in the pathogenesis of CD in Japanese children.
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Affiliation(s)
- Yoshito Fujitake
- Department of Pediatrics and Adolescent Medicine, Juntendo University School of Medicine, Hongo, Tokyo; Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
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Heneghan AF, Pierre JF, Kudsk KA. JAK-STAT and intestinal mucosal immunology. JAKSTAT 2013; 2:e25530. [PMID: 24416649 PMCID: PMC3876429 DOI: 10.4161/jkst.25530] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 06/24/2013] [Accepted: 06/25/2013] [Indexed: 02/06/2023] Open
Abstract
The intestinal mucosal immune system is challenged with bacteria, viruses, and parasites, in addition to food and environmental antigens, that require dynamic immune responsiveness for homeostasis. One central signaling pathway is JAK-STAT, which regulates the adaptive and innate immune arms of mucosal immunity as well as epithelial repair and regeneration. Adaptive immunity includes lymphocyte mediated secretion of specific antibodies, while innate immune respones include secretion of non-antigen specific compounds. This review examines effects of specialized nutrition support on JAK-STAT in innate immune function and in lymphocyte modulation and epithelial antibody transport in gut-associated lymphoid tissue.
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Affiliation(s)
- Aaron F Heneghan
- Department of Surgery; University of Wisconsin-Madison School of Medicine and Public Health; Madison, WI USA
| | - Joseph F Pierre
- Department of Surgery; University of Wisconsin-Madison School of Medicine and Public Health; Madison, WI USA
| | - Kenneth A Kudsk
- Department of Surgery; University of Wisconsin-Madison School of Medicine and Public Health; Madison, WI USA ; Veteran Administration Surgical Service; William S. Middleton Memorial Veterans Hospital; Madison, WI USA
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Accumulation of Mast Cells in the Lesions and Effects of Antiallergic Drugs on the Patients with Inflammatory Bowel Disease. ACTA ACUST UNITED AC 2013. [DOI: 10.1155/2013/714807] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The pathomechanism of inflammatory bowel disease (IBD) has not yet been fully demonstrated. However, it is well known that mast cells are present in the gastrointestinal tract, suggesting that mast cells may take part in it. So, we investigated the number of mast cells in IBD, such as ulcerative colitis (UC) and eosinophilic colitis, and showed that the number of mast cells was increased in the inflammatory lesions. We also presented a case of UC which was treated successfully with an antiallergic drug, tranilast. Furthermore, possible new approaches to treating the disease with immunomodulators including suplatast are introduced. However, our investigations were performed with a limited number of patients with IBD, and additional further studies are required to confirm the findings.
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The immunology and genetics of resistance of sheep to Teladorsagia circumcincta. Vet Res Commun 2013; 37:171-81. [PMID: 23430701 DOI: 10.1007/s11259-013-9559-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2013] [Indexed: 12/24/2022]
Abstract
Teladorsagia circumcincta is one of the most economically important gastrointestinal nematode parasites of sheep in cool temperate regions, to which sheep show genetically-varying resistance to infection. This is a very common parasite and viable sheep production requires the extensive use of anthelmintic drugs. However, the emergence of drug-resistant parasites has stimulated the search for alternative control strategies to curb production losses. Lambs become infected soon after weaning and begin to control parasite burden within 8-10 weeks of continual infection. This control is an acquired characteristic mediated by the development of parasite-specific antibodies. This paper describes the immunology associated with resistance and susceptibility, focussing on differential T cell activation that regulates the production of specific effector mechanisms. It continues by summarizing the methods used to identify genes that could be exploited as molecular markers of selection for resistance. In particular it focusses on the link between understanding the molecular immunology of infection and the identification of candidate genes for selection.
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Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing inflammation afflicting any part of the bowel wall as a result of a deregulated and inappropriate immune response. In recent years, experimental and clinical evidence has demonstrated that infection with parasitic worms could protect hosts from IBD. The aims of this study were to determine if the underlying mechanism of the host immune regulation inherent to Trichinella spiralis infection involves Foxp3-expressing regulatory T cells, and to gain insight about time-related interactions between intestinal nematode infection and induced colitis using an experimental model for ulcerative colitis. Mice were experimentally subjected to acetic acid-induced colitis, which was either preceded or followed by T. spiralis infection. Assessment of colitis was done by histopathological examination of the colon and determination of pentraxin 3 levels. Immunohistochemistry was done for demonstration of Foxp3-expressing regulatory T cells in colonic tissues. It was evident that T. spiralis infection ameliorated the severe inflammation induced by acetic acid, evidenced by amelioration of histopathological changes and diminution of pentraxin 3 levels. The amelioration was more pronounced when T. spiralis infection preceded the induction of colitis. Regarding the immunohistochemical staining of regulatory T cells, T. spiralis infection induced recruitment of Foxp3-expressing regulatory T cells to areas of inflammation. In conclusion, T. spiralis regulatory mechanism can improve inflammation of the colon through the 'inflammatory-regulatory' axis. Finally, it would be of great importance to apply these results to the development of new therapeutic approaches for the treatment of ulcerative colitis.
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Dai SX, Wu G, Zou Y, Feng YL, Liu HB, Feng JS, Chi HG, Lv RX, Zheng XB. Balance of CD8+ CD28+ / CD8+ CD28- T lymphocytes is vital for patients with ulcerative colitis. Dig Dis Sci 2013; 58:88-96. [PMID: 22851040 DOI: 10.1007/s10620-012-2327-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Accepted: 07/17/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND Immune balances are important for many diseases including ulcerative colitis (UC). This study aimed to explore the role of the balance between CD8+ CD28+ and CD8+ CD28- T lymphocytes for the immunological pathogenesis of UC. METHODS Sixteen patients with UC, 16 patients with irritable bowel syndrome (IBS) and 15 healthy volunteers were enrolled. The frequencies of CD8+ CD28+ and CD8+CD28- T lymphocytes in peripheral blood and colon tissue were tested using flow cytometry and immunofluorescent, respectively. The cytokines of the two lymphocytes were detected by protein chips and ELISA. The expression of the signal transducers, the JAK3 and STAT6, as well the transcription factors, the NFATc2 and GATA3, was all detected by both western blot and immunohistochemistry. RESULTS For UC patients, the frequencies of CD8+ CD28+ T lymphocytes, together with the ratios of CD8+ CD28+ / CD8+ CD28- T lymphocytes in blood and colon tissue, were significantly lower than those in both IBS patients and healthy volunteers. But the frequencies of CD8+ CD28- T lymphocytes in blood and colon tissue of the UC patients were significantly higher than the other two groups. The concentration of IL-7 and -13, and the expression of JAK3 and STAT6 in UC patients, were significantly lower when compared with the other two groups. Conversely, the concentration of IL-12p40 and -15, and the expression of GATA3 and NFATc2 in UC patients, were significantly higher than both IBS and control group. CONCLUSIONS The balance of CD8+ CD28+ / CD8+ CD28- T lymphocytes plays a vital role in UC, while the balance tilt towards CD8+ CD28+ T lymphocytes is beneficial for patients with UC.
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Affiliation(s)
- Shi-Xue Dai
- Emergency Department of Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
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41
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Abstract
BACKGROUND Patients with ulcerative colitis (UC) who are in clinical remission may still have underlying endoscopic inflammation, which is associated with inferior clinical outcomes. The goal of this study was to determine the prevalence of active endoscopic disease, and factors associated with it, in patients with UC who are in clinical remission. METHODS Prospective observational study in a single center. Patients with UC in clinical remission (by Simple Clinical Colitis Activity Index) were enrolled prospectively at the time of surveillance colonoscopy. Disease phenotype, endoscopic activity (Mayo subscore), and histologic score (Geboes) were recorded, and blood was drawn for peripheral blood biomarkers. RESULTS Overall, 149 patients in clinical remission were prospectively enrolled in this cohort; 81% had been in clinical remission for >6 months, and 86% were currently prescribed maintenance medications. At endoscopy, 45% of patients in clinical remission had any endoscopic inflammation (Mayo endoscopy subscore >0), and 13% had scores >1. In a multivariate model, variables independently associated with a Mayo endoscopic score >1 were remission for <6 months (P = 0.001), white blood count (P = 0.01), and C-reactive protein level (P = 0.009). A model combining these 3 variables had a sensitivity of 94% and a specificity of 73% for predicting moderate-to-severe endoscopic activity in patients in clinical remission (area under the curve, 0.86). In an unselected subgroup of patients who had peripheral blood mononuclear cell messenger RNA profiling, GATA3 messenger RNA levels were significantly higher in patients with endoscopic activity. CONCLUSIONS Duration of clinical remission, white blood count, and C-reactive protein level can predict the probability of ongoing endoscopic activity, despite clinical remission in patients with UC. These parameters could be used to identify patients who require intensification of treatment to achieve mucosal healing.
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Huang Z, Jiang Y, Yang Y, Shao J, Sun X, Chen J, Dong L, Zhang J. 3,3'-Diindolylmethane alleviates oxazolone-induced colitis through Th2/Th17 suppression and Treg induction. Mol Immunol 2012; 53:335-44. [PMID: 23085552 DOI: 10.1016/j.molimm.2012.09.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Revised: 09/14/2012] [Accepted: 09/23/2012] [Indexed: 12/19/2022]
Abstract
The T cell is pivotal in orchestrating and promoting an immune response during ulcerative colitis (UC). The aryl hydrocarbon receptor (AhR) is involved in the regulation of T cell responses, and 3,3'-diindolylmethane (DIM) is a known ligand of AhR. The aim of this study was to examine the therapeutic effects of DIM in experimental colitis and to investigate the possible mechanisms underlying its effects on mucosal T cell responses. The therapeutic effects of DIM were studied in an oxazolone-induced colitis model. The pathologic markers of colitis were measured, moreover, T-helper cell (Th)- and regulatory T cell (Treg)-related transcription factor expression and associated colonic cytokine production were determined. The impact of DIM on T cell differentiation was further investigated in cultures of naive Th cells that were stimulated with anti-CD3/CD28 monoclonal antibodies (mAbs). The administration of DIM attenuated experimental colitis, as determined by pathological indices. DIM may affect signaling pathways downstream of AhR, leading to decreased Th2/Th17 cells and increased Tregs. Ultimately, this could result in the alleviation of experimental colitis. DIM has shown anti-UC activity in animal models via inhibition of Th2/Th17 cells and promotion of Tregs and may thus offer potential treatments for UC patients.
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Affiliation(s)
- Zhen Huang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China
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Cao XH, Zhang XY, Zhang XN. Progress in understanding the role of interleukins in the pathogenesis of ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2011; 19:3143-3148. [DOI: 10.11569/wcjd.v19.i30.3143] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic, nonspecific inflammatory bowel disease. The assessment of UC reactiveness can be used to guide clinical treatment. Therefore, it is of important significance to find markers which have sufficient specificity and sensitivity for ease of monitoring UC. In recent years, a intensive study of the relation between interleukins (ILs) and the pathogenesis of UC has revealed changes in the secretion levels of ILs in the progression of UC, which suggests that ILs can be used as markers for monitoring the activity of UC to guide diagnosis and treatment. This paper is a review on the mechanism of action of ILs in the pathogenesis of UC.
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Abstract
Measuring cytokine production is an integral part of measuring immune response during immunotherapy. Current technologies allow the simultaneous quantification of multiple cytokines in a variety of tissues. Patterns of cytokine response can be referred to as cytokine profiles. This article discusses the experimental design and data analysis of a number of studies that examined cytokine profiles in humans. We highlight potential sources of variability, both due to assay nuances and the diversity of human populations. We present strategies for analyzing data, emphasizing both multidimensional analysis and the value of treating each donor as his or her own control.
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Affiliation(s)
- Janet C Siebert
- Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Providence Cancer Center, Portland, OR 97213, USA.
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