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Moret-Tatay I, Nos P, Iborra M, Rausell F, Beltrán B. Catalase inhibition can modulate the ability of peripheral blood T cells to undergo apoptosis in Crohn's disease. Clin Exp Immunol 2024; 217:45-56. [PMID: 38247555 PMCID: PMC11188543 DOI: 10.1093/cei/uxad134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 10/12/2023] [Accepted: 12/18/2023] [Indexed: 01/23/2024] Open
Abstract
Crohn's disease (CD) is a chronic relapsing inflammatory disorder in which defective apoptosis of mucosal T cells is postulated to produce sustained inflammation and reactive oxygen species accumulation. Whether CD T cells are intrinsically resistant to apoptosis or whether this resistance is acquired at the intestinal site needs to be clarified, as the cellular mechanisms modulate the impaired apoptosis in these cells. Here, we analysed peripheral blood T cells from patients naïve to specific CD treatment at the onset and from healthy controls. Non-activated freshly purified lymphocytes were cultured and submitted to in vitro protocols for activation (CD3/CD28 antibodies) and apoptosis (Fas antibody). Cells were analysed by flow cytometry. Caspases (3, 8, and 9) and catalase activity were measured; protein levels of bax, Bcl-2, and NF-kB were detected by western blotting, and cytokines by Luminex-based assays. The results showed that CD4 T cells from CD patients are less prone to apoptosis before they can migrate to the intestinal mucosa. Caspase-9, FasR, sIL-2Rα, IL-17A, IFNγ, IL-6, TNF-α, and IL-10 were shown to be significantly different in CD but not for the rest of the analysed biological elements. Catalase activity was significantly reduced in CD T cells, which was confirmed in ex vivo experiments in which catalase inhibition in T cells from healthy controls triggered apoptosis inhibition in a dose-dependent manner. In conclusion, apoptosis inhibition of CD T cells is a feature of these cells before they can migrate to the intestinal mucosa. Noteworthy, the impaired apoptosis of T cells can be directly influenced by catalase inhibition.
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Affiliation(s)
- Inés Moret-Tatay
- Inflammatory Bowel Disease Research Group, Health Research Institute, Hospital La Fe (IIS La Fe), Valencia, Spain
- General Directorate of Public Health, Council of Healthcare, Valencia, Spain
- Biomedical Research Centre, Hepatic and Digestive Diseases Network (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD]), Madrid, Spain
| | - Pilar Nos
- Biomedical Research Centre, Hepatic and Digestive Diseases Network (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD]), Madrid, Spain
- Gastroenterology Unit, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Marisa Iborra
- Biomedical Research Centre, Hepatic and Digestive Diseases Network (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD]), Madrid, Spain
- Gastroenterology Unit, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Francisco Rausell
- Inflammatory Bowel Disease Research Group, Health Research Institute, Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Belén Beltrán
- Biomedical Research Centre, Hepatic and Digestive Diseases Network (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD]), Madrid, Spain
- Gastroenterology Unit, La Fe University and Polytechnic Hospital, Valencia, Spain
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Marafini I, De Cristofaro E, Salvatori S, Calabrese E, Lolli E, Monteleone I, Franchi L, Ciccocioppo R, Glick G, Opipari A, Monteleone G. Niclosamide Enema for Active Distal Ulcerative Colitis: A Phase 1, Open-Label Study. Inflamm Bowel Dis 2024; 30:894-899. [PMID: 37478412 DOI: 10.1093/ibd/izad125] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Indexed: 07/23/2023]
Abstract
BACKGROUND Oral and rectal formulations of 5-aminosalicylic acid are the first-line therapy for mild-to-moderate, distal ulcerative colitis (UC), but such a treatment is not effective in one-third of patients. Niclosamide is a small molecule, developed and approved as an orally administered drug to treat helminthic infections, with an excellent safety profile. Preclinical work showed that niclosamide is an anti-inflammatory agent, thereby providing the rationale to explore its safety and efficacy in patients with UC. This phase 1, open-label trial was aimed at assessing the safety of niclosamide formulated as an enema in patients with mild-to-moderate, distal UC, who relapsed on maintenance therapy with oral and/or rectal 5-aminosalicylic acid. METHODS Seventeen patients with active UC received niclosamide enema (150 mg/60 mL) twice a day for 6 weeks. The primary endpoint was the safety of niclosamide treatment. Secondary endpoints included clinical remission and improvements in endoscopic Mayo/histologic scores. Endoscopic remission percentages exclude participants meeting criteria at baseline for endoscopic remission. RESULTS Niclosamide was well tolerated by all 17 patients that were enrolled and treated. No serious adverse event was registered. Fifteen mild adverse events were registered in 6 patients and considered to be unrelated to the treatment. Clinical remission was achieved in 10 (59%) of 17 patients. Improvements of endoscopic Mayo score and histologic Geboes score were seen in 7 (58%) of 12 and 7 (41.2%) of 17 patients, respectively. CONCLUSIONS Niclosamide enema treatment is safe and well tolerated. Niclosamide improves clinical symptoms and endoscopic/histologic signs of UC; however, appropriately designed placebo-controlled clinical trials are required to confirm efficacy.
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Affiliation(s)
- Irene Marafini
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
| | - Elena De Cristofaro
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
| | - Silvia Salvatori
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
| | - Emma Calabrese
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
| | - Elisabetta Lolli
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
| | - Ivan Monteleone
- University of Michigan, Ann Arbor, MI, USA
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | | | | | - Gary Glick
- University of Michigan, Ann Arbor, MI, USA
| | | | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
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Caio G, Lungaro L, Chiarioni G, Giancola F, Caputo F, Guarino M, Volta U, Testino G, Pellicano R, Zoli G, DE Giorgio R. Beyond biologics: advanced therapies in inflammatory bowel diseases. Minerva Gastroenterol (Torino) 2022; 68:319-332. [PMID: 34309337 DOI: 10.23736/s2724-5985.21.02985-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION Inflammatory bowel diseases (IBDs) are conditions affecting the gut at different levels characterized by an abnormal activation of the intestinal immune system. In this narrative review, we will provide the reader with an update on the efficacy and safety of new pharmacological strategies to treat IBD patients. EVIDENCE ACQUISITION We performed a thorough literature review via PubMed, EMBASE, MEDLINE and Science Direct databases addressing studies reporting on new therapies for IBD management published in the last ten years (January 2010-December 2020). Data from pharmaceutical companies and abstracts of conferences/meetings have also been considered. EVIDENCE SYNTHESIS The discovery of monoclonal antibodies blocking pro-inflammatory cytokines, e.g., tumor necrosis factor-α (TNF-α) radically changed the management of IBDs. Anti-TNF-α agents represent the prototype molecule of "biologics"/"biologicals." These compounds have significantly improved the therapeutic management of IBDs refractory to standard medications as they provide clinical remission, mucosal healing and prevent extra-intestinal manifestations. However, about 50% of patients treated with biologicals experienced drawbacks, including primary failure or loss of response, requiring new effective treatments. Translational studies have identified new strategies, different from the TNF-α blockade, and new molecules, e.g. sphingosine-1-phosphate agonists and the JAK kinase inhibitors, have been proposed as potential therapeutic options for IBDs. CONCLUSIONS With the availability of novel approaches reviewed in this article, physicians and especially gastroenterologists will increase the therapeutic options to provide a better management of IBD patients, particularly those poorly responsive to biologicals.
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Affiliation(s)
- Giacomo Caio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Mucosal Immunology and Biology Research Center, Massachusetts General Hospital-Harvard Medical School, Boston, MA, USA
- Center for the Study and Treatment of Chronic Inflammatory Intestinal Diseases (IBD) and Gastroenterological Manifestations of Rare Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Lisa Lungaro
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Department of Internal Medicine, Santissima Annunziata Hospital, University of Ferrara, Ferrara, Italy
| | - Giuseppe Chiarioni
- Division of Gastroenterology, University Hospital of Verona, Verona, Italy
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Fiorella Giancola
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Fabio Caputo
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Center for the Study and Treatment of Chronic Inflammatory Intestinal Diseases (IBD) and Gastroenterological Manifestations of Rare Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Department of Internal Medicine, Santissima Annunziata Hospital, University of Ferrara, Ferrara, Italy
| | - Matteo Guarino
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Umberto Volta
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Gianni Testino
- Unit of Addiction and Hepatology/Alcohological Regional Centre, ASL3 c/o IRCCS San Martino Hospital, Genoa, Italy
- Italian Society on Alcohol, Bologna, Italy
| | | | - Giorgio Zoli
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Center for the Study and Treatment of Chronic Inflammatory Intestinal Diseases (IBD) and Gastroenterological Manifestations of Rare Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Department of Internal Medicine, Santissima Annunziata Hospital, University of Ferrara, Ferrara, Italy
| | - Roberto DE Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy -
- Center for the Study and Treatment of Chronic Inflammatory Intestinal Diseases (IBD) and Gastroenterological Manifestations of Rare Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
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Characterization of mucosal cytokine profile in ulcerative colitis patients under conventional and anti-TNF-a treatment. Eur J Gastroenterol Hepatol 2020; 32:1527-1532. [PMID: 32976192 DOI: 10.1097/meg.0000000000001933] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Cytokines play a pivotal role in inflammatory bowel disease (IBD). We investigated the expression of inflammatory and regulatory cytokines in inflamed and uninflamed mucosal samples of ulcerative colitis patients. METHODS Twenty-five ulcerative colitis patients were enrolled. Bioptic samples from inflamed and not inflamed intestinal areas were obtained. Multiplex analysis for inflammatory and regulatory cytokines was performed. Serum C-reactive protein (CRP) was assessed. Endoscopic Mayo score and histological simplified Geboes score were calculated. RESULTS Interleukin (IL)-1Ra, IL-6, IL-8, IL-17, induced Protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1a, MIP-1b resulted increased in ulcerative colitis inflamed vs ulcerative colitis not inflamed areas. No differences were registered between conventional and anti-tumor necrosis factor-a regimens. No difference with CRP levels was found. IL-7 resulted reduced in patients with endoscopic Mayo score ≥2. All the not inflamed samples had a Geboes score <2A, while all the inflamed specimens had a Geboes score ≥2B. IL-1Ra resulted increased in the group with a Geboes score ≥4. CONCLUSIONS Inflamed and adjacent not inflamed mucosal areas in ulcerative colitis patients share detailed inflammatory molecular pathways, but can be differentiated endoscopically and histologically on the basis of specific cytokines levels. This underlines the complexity of the mucosal cytokine network in ulcerative colitis and highlights the major limitations of a single proinflammatory target therapeutic strategy in IBD.
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Hsiao YH, Ho CT, Pan MH. Bioavailability and health benefits of major isoflavone aglycones and their metabolites. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104164] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Coletta M, Paroni M, Alvisi MF, De Luca M, Rulli E, Mazza S, Facciotti F, Lattanzi G, Strati F, Abrignani S, Fantini MC, Vecchi M, Geginat J, Caprioli F. Immunological Variables Associated With Clinical and Endoscopic Response to Vedolizumab in Patients With Inflammatory Bowel Diseases. J Crohns Colitis 2020; 14:1190-1201. [PMID: 32100016 DOI: 10.1093/ecco-jcc/jjaa035] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND AND AIMS Vedolizumab [VDZ] is a monoclonal antibody directed against the α4β7 integrin heterodimer, approved for patients with inflammatory bowel diseases [IBD]. This study aimed at identifying immunological variables associated with response to vedolizumab in patients with ulcerative colitis [UC] and Crohn's disease [CD]. METHODS This is a phase IV explorative prospective interventional trial. IBD patients received open-label VDZ at Weeks 0, 2, 6, and 14. Patients with a clinical response at Week 14 were maintained with VDZ up to Week 54. At Weeks 0 and 14, their peripheral blood was obtained and endoscopy with biopsies was performed. The Week 14 clinical response and remission, Week 54 clinical remission, and Week 14 endoscopic response were evaluated as endpoints of the study. The expression of surface markers, chemokine receptors, and α4β7 heterodimer in peripheral blood and lamina propria lymphocytes was assessed by flow cytometry. A panel of soluble mediators was assessed in sera at baseline and at Week 14 by 45-plex. RESULTS A total of 38 IBD patients [20 UC, 18 CD] were included in the study. At Week 14, the clinical response and remission rates were 87% and 66%, respectively. Higher baseline levels of circulating memory Th1 cells were strongly associated with clinical response at Week 14 [p = 0.0001], whereas reduced baseline levels of lamina propria memory Th17 and Th1/17 cells were associated with endoscopic response. Immunological clusters were found to be independently associated with vedolizumab outcomes at multivariable analysis. A panel of soluble markers, including IL17A, TNF, CXCL1, CCL19 for CD and G-CSF and IL7 for UC, associated with vedolizumab-induced Week 54 clinical remission. CONCLUSIONS The results of this exploratory study uncovered a panel of circulating and mucosal immunological variables associated with response to treatment with vedolizumab.
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Affiliation(s)
- Marina Coletta
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Moira Paroni
- Istituto Nazionale di Genetica Molecolare 'Enrica ed Romeo Invernizzi' [INGM], Milan, Italy.,Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - Maria Francesca Alvisi
- Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Matilde De Luca
- Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Eliana Rulli
- Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Stefano Mazza
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Federica Facciotti
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Georgia Lattanzi
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Francesco Strati
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Sergio Abrignani
- Istituto Nazionale di Genetica Molecolare 'Enrica ed Romeo Invernizzi' [INGM], Milan, Italy.,Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | | | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Jens Geginat
- Istituto Nazionale di Genetica Molecolare 'Enrica ed Romeo Invernizzi' [INGM], Milan, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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An Integrated Genomic and Transcriptomic Analysis Reveals Candidates of Susceptibility Genes for Crohn's Disease in Japanese Populations. Sci Rep 2020; 10:10236. [PMID: 32581322 PMCID: PMC7314801 DOI: 10.1038/s41598-020-66951-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 06/01/2020] [Indexed: 01/01/2023] Open
Abstract
Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD.
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8
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Schleier L, Wiendl M, Heidbreder K, Binder MT, Atreya R, Rath T, Becker E, Schulz-Kuhnt A, Stahl A, Schulze LL, Ullrich K, Merz SF, Bornemann L, Gunzer M, Watson AJM, Neufert C, Atreya I, Neurath MF, Zundler S. Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing. Gut 2020; 69:252-263. [PMID: 31092589 DOI: 10.1136/gutjnl-2018-316772] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 04/12/2019] [Accepted: 04/17/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To study the role of α4β7 integrin for gut homing of monocytes and to explore the biological consequences of therapeutic α4β7 inhibition with regard to intestinal wound healing. DESIGN We studied the expression of homing markers on monocyte subsets in the peripheral blood and on macrophage subsets in the gut of patients with IBD and controls with flow cytometry and immunohistochemistry. Integrin function was addressed with dynamic adhesion assays and in vivo gut homing assays. In vivo wound healing was studied in mice deficient for or depleted of α4β7 integrin. RESULTS Classical and non-classical monocytes were clearly dichotomous regarding homing marker expression including relevant expression of α4β7 integrin on human and mouse non-classical monocytes but not on classical monocytes. Monocyte-expressed α4β7 integrin was functionally important for dynamic adhesion to mucosal vascular addressin cell adhesion molecule 1 and in vivo gut homing. Impaired α4β7-dependent gut homing was associated with reduced (effect size about 20%) and delayed wound healing and suppressed perilesional presence of wound healing macrophages. Non-classical monocytes in the peripheral blood were increased in patients with IBD under clinical treatment with vedolizumab. CONCLUSION In addition to reported effects on lymphocytes, anti-α4β7 therapy in IBD also targets non-classical monocytes. Impaired gut homing of such monocytes might lead to a reduction of wound healing macrophages and could potentially explain increased rates of postoperative complications in vedolizumab-treated patients, which have been observed in some studies.
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Affiliation(s)
- Lena Schleier
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Maximilian Wiendl
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Karin Heidbreder
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Marie-Theres Binder
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Timo Rath
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Emily Becker
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Anja Schulz-Kuhnt
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Annette Stahl
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Lisa Lou Schulze
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Karen Ullrich
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Simon F Merz
- Institute of Experimental Immunology and Imaging, University Duisburg-Essen and University Hospital Essen, Essen, Germany
| | - Lea Bornemann
- Institute of Experimental Immunology and Imaging, University Duisburg-Essen and University Hospital Essen, Essen, Germany
| | - Matthias Gunzer
- Institute of Experimental Immunology and Imaging, University Duisburg-Essen and University Hospital Essen, Essen, Germany
| | - Alastair J M Watson
- Norwich Medical School, Norwich Research Park, University of East Anglia, Norwich, UK
| | - Clemens Neufert
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Imke Atreya
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Sebastian Zundler
- Department of Medicine 1, Kussmaul Campus for Medical Research & Translational Research Center, University of Erlangen-Nuremberg, Erlangen, Germany
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Chaparro M, Aterido A, Guerra I, Iborra M, Cabriada JL, Bujanda L, Taxonera C, García-Sánchez V, Marín-Jiménez I, Barreiro-de Acosta M, Vera I, Martín-Arranz MD, Hernández-Breijo B, Mesonero F, Sempere L, Gomollón F, Hinojosa J, Bermejo F, Beltrán B, Rodríguez-Pescador A, Banales JM, Olivares D, Aguilar-Melero P, Menchén L, Ferreiro-Iglesias R, Blazquez Gómez I, Benitez García B, Guijarro LG, Marin AC, Bernardo D, Marsal S, Julia A, Gisbert JP. Functional rare variants influence the clinical response to anti-TNF therapy in Crohn's disease. Therap Adv Gastroenterol 2019; 12:1756284819867848. [PMID: 31598133 PMCID: PMC6764039 DOI: 10.1177/1756284819867848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 06/28/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The effect of low-frequency functional variation on anti-tumor necrosis factor alpha (TNF) response in Crohn's disease (CD) patients remains unexplored. The objective of this study was to investigate the impact of functional rare variants in clinical response to anti-TNF therapy in CD. METHODS CD anti-TNF naïve patients starting anti-TNF treatment due to active disease [Crohn's Disease Activity Index (CDAI > 150)] were included. The whole genome was sequenced using the Illumina Hiseq4000 platform. Clinical response was defined as a CDAI score <150 at week 14 of anti-TNF treatment. Low-frequency variants were annotated and classified according to their damaging potential. The whole genome of CD patients was screened to identify homozygous loss-of-function (LoF) variants. The TNF signaling pathway was tested for overabundance of damaging variants using the SKAT-O method. Functional implication of the associated rare variation was evaluated using cell-type epigenetic enrichment analyses. RESULTS A total of 41 consecutive CD patients were included; 3250 functional rare variants were identified (2682 damaging and 568 LoF variants). Two homozygous LoF mutations were found in HLA-B and HLA-DRB1 genes associated with lack of response and remission, respectively. Genome-wide LoF variants were enriched in epigenetic marks specific for the gastrointestinal tissue (colon, p = 4.11e-4; duodenum, p = 0.011). The burden of damaging variation in the TNF signaling pathway was associated with response to anti-TNF therapy (p = 0.016); damaging variants were enriched in epigenetic marks from CD8+ (p = 6.01e-4) and CD4+ (p = 0.032) T cells. CONCLUSIONS Functional rare variants are involved in the response to anti-TNF therapy in CD. Cell-type enrichment analysis suggests that the gut mucosa and CD8+ T cells are the main mediators of this response.
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Affiliation(s)
- María Chaparro
- Gastroenterology Unit. Hospital Universitario de
La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP),
Universidad Autónoma de Madrid, 62. 28006 Madrid, Spain
| | - Adrià Aterido
- Rheumatology Research Group, Vall d’Hebron
Research Institute, Barcelona, Spain
- Department of Experimental and Health Sciences,
Universitat Pompeu Fabra, Barcelona, Spain
| | - Iván Guerra
- Gastroenterology Unit, Hospital Universitario de
Fuenlabrada, Instituto de Investigación de Hospital La Paz (IdiPaz), Madrid,
Spain
| | - Marisa Iborra
- Gastroenterology Unit, Hospital Universitario de
La Fe, Valencia, Spain
| | - Jose Luis Cabriada
- Gastroenterology Unit, Hospital Universitario de
Galdakano, Vizcaya, Spain
| | - Luis Bujanda
- Gastroenterology Unit, Hospital Universitario de
Donostia, Instituto Biodonostia, UPV/EHU, Ikerbasque, Guipúzcoa, Spain
| | - Carlos Taxonera
- Gastroenterology Unit, Hospital Universitario
Clínico San Carlos and IdISSC, Madrid, Spain
| | - Valle García-Sánchez
- Gastroenterology Unit, Instituto Maimónides de
Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina
Sofía/Universidad de Córdoba, Spain
| | - Ignacio Marín-Jiménez
- Gastroenterology Unit, Hospital Universitario
Gregorio Marañón e IiSGM, Madrid, Spain
| | | | - Isabel Vera
- Gastroenterology Unit, Hospital Universitario
Puerta de Hierro Majadahonda, Madrid, Spain
| | | | - Borja Hernández-Breijo
- Universidad de Alcalá, Alcalá de Henares,
Spain
- Immuno-Rheumatology Research Group. IdiPaz.
Hospital Universitario La Paz, Madrid, Spain
| | - Francisco Mesonero
- Gastroenterology Unit, Hospital Universitario
Ramón y Cajal, Madrid, Spain
| | - Laura Sempere
- Gastroenterology Unit, Hospital Universitario
Alicante, Alicante, Spain
| | - Fernando Gomollón
- Gastroenterology Unit, Hospital Clínico
Universitario, Lozano Blesa, IIS Aragón, Zaragoza, Spain
| | - Joaquín Hinojosa
- Gastroenterology Unit, Hospital Universitario
Manises, Valencia, Spain
| | - Fernando Bermejo
- Gastroenterology Unit, Hospital Universitario
de Fuenlabrada, Instituto de Investigación de Hospital La Paz (IdiPaz),
Madrid, Spain
| | - Belén Beltrán
- Gastroenterology Unit, Hospital Universitario
de La Fe, Valencia, Spain
| | | | - Jesús María Banales
- Gastroenterology Unit, Hospital Universitario
de Donostia, Instituto Biodonostia, UPV/EHU, Ikerbasque, Guipúzcoa,
Spain
| | - David Olivares
- Gastroenterology Unit, Hospital Universitario
Clínico San Carlos and IdISSC, Madrid, Spain
| | - Patricia Aguilar-Melero
- Gastroenterology Unit, Instituto Maimónides de
Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina
Sofía/Universidad de Córdoba, Spain
| | - Luis Menchén
- Gastroenterology Unit, Hospital Universitario
Gregorio Marañón e IiSGM, Madrid, Spain
| | - Rocío Ferreiro-Iglesias
- Gastroenterology Unit, Hospital Universitario
Clínico de Santiago, Santiago de Compostela, Spain
| | - Isabel Blazquez Gómez
- Gastroenterology Unit, Hospital Universitario
Puerta de Hierro Majadahonda, Madrid, Spain
| | | | | | - Alicia C Marin
- Gastroenterology Unit, Hospital Universitario
de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP),
Universidad Autónoma de Madrid, Spain
| | - David Bernardo
- Gastroenterology Unit, Hospital Universitario
de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP),
Universidad Autónoma de Madrid, Spain
| | - Sara Marsal
- Rheumatology Research Group, Vall d’Hebron
Research Institute, Barcelona, Spain
| | - Antonio Julia
- Rheumatology Research Group, Vall d’Hebron
Research Institute, Barcelona, Spain
| | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario
de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP),
Universidad Autónoma de Madrid, Spain
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10
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Martinez-Fierro ML, Garza-Veloz I, Rocha-Pizaña MR, Cardenas-Vargas E, Cid-Baez MA, Trejo-Vazquez F, Flores-Morales V, Villela-Ramirez GA, Delgado-Enciso I, Rodriguez-Sanchez IP, Ortiz-Castro Y. Serum cytokine, chemokine, and growth factor profiles and their modulation in inflammatory bowel disease. Medicine (Baltimore) 2019; 98:e17208. [PMID: 31567972 PMCID: PMC6756690 DOI: 10.1097/md.0000000000017208] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Ulcerative colitis (UC) and Crohn disease (CD) are the most common forms of inflammatory bowel disease (IBD). Because these subtypes of IBD are characterized by periods of activity and remission, an understanding of the modulation of biochemical markers with the clinical features of IBD or its treatment, may be useful for determining the correct treatment protocol.This study aimed to evaluate the serum levels of 27 protein biomarkers to determine their association with IBD, correlation with clinical findings of disease, and modulation according to the pharmacologic therapy.A case-control study was carried out in Zacatecas, Mexico. The 27 protein profiles of serum from 53 participants (23 UC, 11 CD, and 19 controls) were evaluated using the Pro Human Cytokine 27-Plex immunoassay (Bio-Rad).Considering the controls as a reference, the group with IBD endoscopic activity showed higher serum levels of granulocyte colony-stimulating factor (G-CSF), interleukin 1 receptor antagonist (IL-1Ra), and platelet-derived growth factor BB (PDGF-BB) (P < .05). Interferon-induced protein 10 (IP-10) was associated with extraintestinal symptoms of disease (P = .041). Both PDGF-BB and interleukin 6 (IL-6) showed the strongest correlations with clinical features of IBD. Levels of IL-6, IL-7, and monocyte chemoattractant protein 1 were higher with 5-aminosalicylic acid (5-ASA) + Azathioprine therapy than controls (P < .05). Combined therapy with 5-ASA + Adalimumab led to the strongest changes in marker modulation: IL-4, IL-5, IL-15, and PDGF-BB, were upregulated (P < .05).Elevated serum levels of G-CSF, IL-1Ra, and PDGF-BB were associated with IBD endoscopic activity, and of IP-10 with extraintestinal manifestations of IBD. Combined therapy of 5-ASA + Adalimumab produced significant upregulation of IL-4, IL-5, IL-15, and PDGF-BB. This information may be useful for deciding on the course of pharmacologic therapy for patients with IBD and for generating new therapy alternatives to improve the outcome of patients with IBD.
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Affiliation(s)
- Margarita L. Martinez-Fierro
- Molecular Medicine Laboratory, Unidad Academica de Medicina Humana y CS
- Posgrado en Ingenieria y Tecnologia Aplicada, Unidad Academica de Ingenieria Electrica, Universidad Autonoma de Zacatecas, Zacatecas
| | - Idalia Garza-Veloz
- Molecular Medicine Laboratory, Unidad Academica de Medicina Humana y CS
- Posgrado en Ingenieria y Tecnologia Aplicada, Unidad Academica de Ingenieria Electrica, Universidad Autonoma de Zacatecas, Zacatecas
| | | | - Edith Cardenas-Vargas
- Molecular Medicine Laboratory, Unidad Academica de Medicina Humana y CS
- Hospital General Zacatecas “Luz González Cosío”, Servicios de Salud de Zacatecas
| | | | - Fabiola Trejo-Vazquez
- Molecular Medicine Laboratory, Unidad Academica de Medicina Humana y CS
- Hospital General de Zacatecas, Instituto de Seguridad y Servicios Sociales para los Trabajadores del Estado (ISSSTE)
| | - Virginia Flores-Morales
- Laboratorio de Sintesis Asimetrica y Bioenergetica (LSAyB), Ingenieria Quimica, Universidad Autonoma de Zacatecas, Zacatecas
| | - Gabriela A. Villela-Ramirez
- Molecular Medicine Laboratory, Unidad Academica de Medicina Humana y CS
- Posgrado en Ingenieria y Tecnologia Aplicada, Unidad Academica de Ingenieria Electrica, Universidad Autonoma de Zacatecas, Zacatecas
| | - Ivan Delgado-Enciso
- School of Medicine, University of Colima, and Cancerology State Institute, Colima State Health Services, Colima
| | - Iram P. Rodriguez-Sanchez
- Laboratorio de Fisiologia Molecular y Estructural, Facultad de Ciencias Biologicas, Universidad Autonoma de Nuevo Leon, Monterrey Nuevo Leon, Mexico
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11
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Abstract
Inflammatory bowel disease is a chronic nonspecific inflammatory disease of the intestine. Its pathogenesis is not yet fully understood. It may be related to heredity, environmental triggers, infection, immune dysfunction and other factors. Purinergic receptor (P2X7R) ligand-gated ion channel is closely related to inflammation and widely expressed in intestinal cells. Previous studies have shown that ATP/P2X7R signal is involved in the pathogenesis of intestinal inflammation, but its specific mechanism needs further study. This article reviews the research progress of P2X7 receptor in inflammatory bowel disease.
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Affiliation(s)
- Yajun Liu
- a Department of Gastroenterology , Xiangya Hospital, Central South University , Changsha , China
| | - Xiaowei Liu
- a Department of Gastroenterology , Xiangya Hospital, Central South University , Changsha , China
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12
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Li Q, Shan Q, Sang X, Zhu R, Chen X, Cao G. Total Glycosides of Peony Protects Against Inflammatory Bowel Disease by Regulating IL-23/IL-17 Axis and Th17/Treg Balance. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:177-201. [PMID: 30612460 DOI: 10.1142/s0192415x19500095] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a group of autoimmune diseases, including ulcerative colitis and Crohn’s disease, characterized by nonspecific inflammation in the gut. Total glycoside of peony (TGP) has been widely used for treatment of autoimmune diseases because of its pharmacological effects. However, it is lack of depth in whether TGP regulate T helper 17 cell (Th17) / T regulatory cell (Treg) immune balance or interleukin 23 (IL-23) / IL-17 axis to achieve the goal of treating IBD. Hence, the aim of this study was to investigate the effects of TGP on experimental colitis mice and the related mechanisms. In the present study, we demonstrated that administration of TGP effectively attenuates colonic inflammation of TNBS-induced colitis mice, mainly reflected in significantly improved clinical parameters, reduced inflammatory response and myeloperoxidase (MPO) activity, even stronger systemic immune ability and effective improvement of Th17/Treg immune disorders. In addition, there was a stronger immunosuppressive ability in a positive cluster of differentiation 4 (CD4[Formula: see text]) T-lymphocytes from the TGP treated mouse colon, characterized by the inhibition of high levels of inflammatory factors and increased regulatory T cells. Importantly, high-dose TGP has similar therapeutic effects as salicylazosulfapyridine (SASP) on IBD treatment. The potential mechanisms might be, at least in part, related to the adjustment of imbalance of Th17/Treg cells and the inhibition of IL-23/IL17 inflammatory signal axis.
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Affiliation(s)
- Qinglin Li
- Zhejiang Cancer Hospital, Hangzhou 310022, P. R. China
| | - Qiyuan Shan
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xianan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Ruyi Zhu
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Xiaocheng Chen
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, P. R. China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, P. R. China
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13
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Zhou G, Wu W, Yu L, Yu T, Yang W, Wang P, Zhang X, Cong Y, Liu Z. Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting TH1/TH17 cell differentiation in patients with inflammatory bowel diseases. J Allergy Clin Immunol 2018; 142:1218-1228.e12. [DOI: 10.1016/j.jaci.2017.09.038] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 08/26/2017] [Accepted: 09/12/2017] [Indexed: 01/18/2023]
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14
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Smids C, Horjus Talabur Horje CS, Drylewicz J, Roosenboom B, Groenen MJM, van Koolwijk E, van Lochem EG, Wahab PJ. Intestinal T Cell Profiling in Inflammatory Bowel Disease: Linking T Cell Subsets to Disease Activity and Disease Course. J Crohns Colitis 2018; 12:465-475. [PMID: 29211912 DOI: 10.1093/ecco-jcc/jjx160] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Accepted: 11/23/2017] [Indexed: 12/20/2022]
Abstract
INTRODUCTION A dysregulated intestinal T cell response is presumed in patients with inflammatory bowel disease [IBD]. In this longitudinal study, we investigated the changes in intestinal T lymphocyte subsets in IBD at first presentation and over time during endoscopic active or inactive disease, and relate them to disease activity and outcome. METHODS We included 129 newly diagnosed patients (87 Crohn's disease [CD], 42 ulcerative colitis [UC]) and 19 healthy controls [HC]. Follow-up biopsy specimens were analysed from 70 IBD patients. Immunophenotyping of specimens was performed by flow cytometry identifying lymphocyte subpopulations. RESULTS IBD patients at diagnosis displayed higher percentages of CD4 T+ cells, Tregs, and central memory T cells [TCM] and with lower percentages of CD8 and CD103 T lymphocytes than HC. Follow-up specimens of patients with endoscopic inactive disease showed T cell subset recovery comparable to HC. Endoscopic active disease at follow-up coincided with T cell subsets similar to those at diagnosis. In UC, lower baseline percentages of CD3 cells was associated with milder disease course without the need of an immunomodulator, whereas in CD, higher baseline percentages of CD4 and Tregs were associated with complicated disease course. CONCLUSIONS The intestinal T cell infiltrate in IBD patients with active endoscopic disease is composed of increased percentages of CD4+ T cells, Tregs, and TCM, with lower percentages of CD8+ T cells and CD103+ T cells, compared with HC and endoscopic inactive IBD. Baseline percentages of CD3, CD4, and Tregs were associated with disease outcome. Further research is needed to demonstrate the predictive value of these lymphocyte subsets.
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Affiliation(s)
- Carolijn Smids
- Crohn and Colitis Centre Rijnstate, Rijnstate Hospital, Arnhem, The Netherlands
| | | | - Julia Drylewicz
- Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Britt Roosenboom
- Crohn and Colitis Centre Rijnstate, Rijnstate Hospital, Arnhem, The Netherlands
| | - Marcel J M Groenen
- Crohn and Colitis Centre Rijnstate, Rijnstate Hospital, Arnhem, The Netherlands
| | - Elly van Koolwijk
- Department of Microbiology and Immunology, Rijnstate Hospital, Arnhem, The Netherlands
| | - Ellen G van Lochem
- Department of Microbiology and Immunology, Rijnstate Hospital, Arnhem, The Netherlands
| | - Peter J Wahab
- Crohn and Colitis Centre Rijnstate, Rijnstate Hospital, Arnhem, The Netherlands
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15
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Chiba H, Kakuta Y, Kinouchi Y, Kawai Y, Watanabe K, Nagao M, Naito T, Onodera M, Moroi R, Kuroha M, Kanazawa Y, Kimura T, Shiga H, Endo K, Negoro K, Nagasaki M, Unno M, Shimosegawa T. Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease. PLoS One 2018; 13:e0194036. [PMID: 29547621 PMCID: PMC5856270 DOI: 10.1371/journal.pone.0194036] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 02/25/2018] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs. For this, we determined cis-regulated allele-specific DNA methylation (ASM) around IBD susceptibility genes in CD4+ effector/memory T cells (Tem) in lamina propria mononuclear cells (LPMCs) in patients with IBD and examined the association between the ASM SNP genotype and neighboring susceptibility gene expressions. METHODS CD4+ effector/memory T cells (Tem) were isolated from LPMCs in 15 Japanese IBD patients (ten Crohn's disease [CD] and five ulcerative colitis [UC] patients). ASM analysis was performed by methylation-sensitive SNP array analysis. We defined ASM as a changing average relative allele score ([Formula: see text]) >0.1 after digestion by methylation-sensitive restriction enzymes. Among SNPs showing [Formula: see text] >0.1, we extracted the probes located on tag-SNPs of 200 IBD susceptibility loci and around IBD susceptibility genes as candidate ASM SNPs. To validate ASM, bisulfite-pyrosequencing was performed. Transcriptome analysis was examined in 11 IBD patients (seven CD and four UC patients). The relation between rs36221701 genotype and neighboring gene expressions were analyzed. RESULTS We extracted six candidate ASM SNPs around IBD susceptibility genes. The top of [Formula: see text] (0.23) was rs1130368 located on HLA-DQB1. ASM around rs36221701 ([Formula: see text] = 0.14) located near SMAD3 was validated using bisulfite pyrosequencing. The SMAD3 expression was significantly associated with the rs36221701 genotype (p = 0.016). CONCLUSIONS We confirmed the existence of cis-regulated ASM around IBD susceptibility genes and the association between ASM SNP (rs36221701) genotype and SMAD3 expression, a susceptibility gene for IBD. These results give us supporting evidence that DNA methylation mediates genetic effects on disease susceptibility.
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Affiliation(s)
- Hirofumi Chiba
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshitaka Kinouchi
- Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan
| | - Yosuke Kawai
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Kazuhiro Watanabe
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Munenori Nagao
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takeo Naito
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Motoyuki Onodera
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Rintaro Moroi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masatake Kuroha
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshitake Kanazawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoya Kimura
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hisashi Shiga
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Katsuya Endo
- Division of Gastroenterology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Kenichi Negoro
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masao Nagasaki
- Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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16
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Markovic BS, Kanjevac T, Harrell CR, Gazdic M, Fellabaum C, Arsenijevic N, Volarevic V. Molecular and Cellular Mechanisms Involved in Mesenchymal Stem Cell-Based Therapy of Inflammatory Bowel Diseases. Stem Cell Rev Rep 2017; 14:153-165. [DOI: 10.1007/s12015-017-9789-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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17
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Zundler S, Schillinger D, Fischer A, Atreya R, López-Posadas R, Watson A, Neufert C, Atreya I, Neurath MF. Blockade of αEβ7 integrin suppresses accumulation of CD8 + and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo. Gut 2017; 66:1936-1948. [PMID: 27543429 DOI: 10.1136/gutjnl-2016-312439] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 07/21/2016] [Accepted: 07/24/2016] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of antiadhesion compounds are incompletely understood. We investigated the role of αEβ7 and α4β7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut. DESIGN We explored integrin expression in patients with IBD by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanised mouse model in dextran sodium sulfate-treated immunodeficient mice. RESULTS High expression of αEβ7 was noted on CD8+ and CD4+ Th9 cells, while α4β7 was expressed on CD8+, Th2 and Th17 cells. T cell receptor stimulation and transforming growth factor β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8+ T cells from patients with IBD under vedolizumab therapy. CONCLUSIONS AEβ7 is of key relevance for gut trafficking of IBD CD8+ T cells and CD4+ Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of αEβ7 in addition to α4β7 may be particularly effective in intestinal disorders with expansion of CD8+ and Th9 cells such as IBD.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Daniela Schillinger
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Anika Fischer
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Rocío López-Posadas
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Alastair Watson
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Clemens Neufert
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Imke Atreya
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
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18
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Zundler S, Becker E, Weidinger C, Siegmund B. Anti-Adhesion Therapies in Inflammatory Bowel Disease-Molecular and Clinical Aspects. Front Immunol 2017; 8:891. [PMID: 28804488 PMCID: PMC5532375 DOI: 10.3389/fimmu.2017.00891] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 07/12/2017] [Indexed: 12/22/2022] Open
Abstract
The number of biologicals for the therapy of immunologically mediated diseases is constantly growing. In contrast to other agents that were previously introduced in rheumatologic or dermatologic diseases and only later adopted for the treatment of inflammatory bowel diseases (IBDs), the field of IBD was ground breaking for the concept of anti-adhesion blockade. Anti-adhesion antibodies selectively target integrins controlling cell homing to the intestine, which leads to reduction of inflammatory infiltration to the gut in chronic intestinal inflammation. Currently, the anti-α4β7-antibody vedolizumab is successfully used for both Crohn's disease and ulcerative colitis worldwide. In this mini-review, we will summarize the fundamental basis of intestinal T cell homing and explain the molecular groundwork underlying current and potential future anti-adhesion therapies. Finally, we will comment on noteworthy clinical aspects of anti-adhesion therapy and give an outlook to the future of anti-integrin antibodies and inhibitors.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1, University of Erlangen-Nuremberg, Translational Research Center, Erlangen, Germany
| | - Emily Becker
- Department of Medicine 1, University of Erlangen-Nuremberg, Translational Research Center, Erlangen, Germany
| | - Carl Weidinger
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-University Medicine, Berlin, Germany
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19
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Azathioprine with Allopurinol: Lower Deoxythioguanosine in DNA and Transcriptome Changes Indicate Mechanistic Differences to Azathioprine Alone. Inflamm Bowel Dis 2017; 23:946-955. [PMID: 28452864 PMCID: PMC5436732 DOI: 10.1097/mib.0000000000001131] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Use of azathioprine (AZA) for inflammatory bowel disease is limited by side effects or poor efficacy. Combining low-dose azathioprine with allopurinol (LDAA) bypasses side effects, improves efficacy, and may be appropriate as first-line therapy. We test the hypothesis that standard-dose azathioprine (AZA) and LDAA treatments work by similar mechanisms, using incorporation of the metabolite deoxythioguanosine into patient DNA, white-blood cell counts, and transcriptome analysis as biological markers of drug effect. METHODS DNA was extracted from peripheral whole-blood from patients with IBD treated with AZA or LDAA, and analyzed for DNA-incorporated deoxythioguanosine. Measurement of red-blood cell thiopurine metabolites was part of usual clinical practice, and pre- and on-treatment (12 wk) blood samples were used for transcriptome analysis. RESULTS There were no differences in reduction of white-cell counts between the 2 treatment groups, but patients on LDAA had lower DNA-incorporated deoxythioguanosine than those on AZA; for both groups, incorporated deoxythioguanosine was lower in patients on thiopurines for 24 weeks or more (maintenance of remission) compared to patients treated for less than 24 weeks (achievement of remission). Patients on LDAA had higher levels of red-blood cell thioguanine nucleotides than those on AZA, but there was no correlation between these or their methylated metabolites, and incorporated deoxythioguanosine. Transcriptome analysis suggested down-regulation of immune responses consistent with effective immunosuppression in patients receiving LDAA, with evidence for different mechanisms of action between the 2 therapies. CONCLUSIONS LDAA is biologically effective despite lower deoxythioguanosine incorporation into DNA, and has different mechanisms of action compared to standard-dose azathioprine.
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20
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Wang S, Qin C. Interleukin 35 Rescues Regulatory B Cell Function, but the Effect Is Dysregulated in Ulcerative Colitis. DNA Cell Biol 2017; 36:413-421. [PMID: 28398870 DOI: 10.1089/dna.2016.3570] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Shaoxuan Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
- Department of Gastroenterology, The First People's Hospital of Jining, Jining, China
| | - Chengyong Qin
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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Billmeier U, Dieterich W, Neurath MF, Atreya R. Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J Gastroenterol 2016; 22:9300-9313. [PMID: 27895418 PMCID: PMC5107694 DOI: 10.3748/wjg.v22.i42.9300] [Citation(s) in RCA: 161] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 09/15/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023] Open
Abstract
Anti-tumor necrosis factor (TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases (IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn’s disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each anti-TNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membrane-bound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with anti-TNF antibodies in chronic intestinal inflammation, by predicting response to therapy.
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Abstract
PURPOSE OF REVIEW Standard structural imaging procedures such as endoscopy, ultrasonography, or MRI are an integral part of the rational management of patients with inflammatory bowel diseases (IBDs). There is nevertheless the need for further refined imaging approaches that are able to overcome the limitations of currently used formats. The advent of molecular imaging modalities that allow real-time visualization of cellular processes not only in the preclinical setting but also in clinical trials has demonstrated its ability to improve current therapeutic strategies. The purpose of this review is to present and discuss advancements in the field of molecular imaging approaches in the IBD field. RECENT FINDINGS Recent preclinical and clinical studies have addressed the applicability of molecular imaging for improving the differentiation between benign and malignant mucosal alterations, increasing the detection of dysplastic intestinal lesions, and predicting individual responses to biological therapies. SUMMARY Molecular imaging in IBD represents an exciting and evolving field that has the potential to impact on current diagnostic and therapeutic algorithms in the treatment of IBD patients by analyzing and visualizing the molecular mechanisms that drive mucosal inflammation. It might enable us to base individualized therapeutic decisions on preceded molecular level analysis by suitable imaging modalities.
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Haemophagocytic lymphohistiocytosis in inflammatory bowel disease with virus infection. GASTROENTEROLOGY REVIEW 2015; 10:78-82. [PMID: 26557937 PMCID: PMC4631275 DOI: 10.5114/pg.2015.48995] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 09/07/2014] [Accepted: 10/28/2014] [Indexed: 12/13/2022]
Abstract
Patients with inflammatory bowel disease (IBD) are at risk of developing haemophagocytic lymphohistiocytosis (HLH) because of chronic systemic inflammation as well as exposure to immunosuppressive medications. The two main causes of HLH in IBD patients are infection with cytomegalovirus and Epstein-Barr virus. Patients with Crohn's disease are more susceptible to HLH than those with ulcerative colitis. The majority of cases are seen in people receiving an immunosuppressive regimen that included thiopurines.
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Erben U, Pawlowski NN, Doerfel K, Loddenkemper C, Hoffmann JC, Siegmund B, Kühl AA. Targeting human CD2 by the monoclonal antibody CB.219 reduces intestinal inflammation in a humanized transfer colitis model. Clin Immunol 2015; 157:16-25. [DOI: 10.1016/j.clim.2015.01.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 12/18/2014] [Accepted: 01/02/2015] [Indexed: 01/12/2023]
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Affiliation(s)
- Samuel Bertin
- University of California, San Diego, Department of Medicine, Stein Clinical Research, Room 126, 9500 Gilman Drive, La Jolla, CA 92093-0663, États-Unis
| | - Eyal Raz
- University of California, San Diego, Department of Medicine, Stein Clinical Research, Room 126, 9500 Gilman Drive, La Jolla, CA 92093-0663, États-Unis
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Role of DOR-β-arrestin1-Bcl2 signal transduction pathway and intervention effects of oxymatrine in ulcerative colitis. ACTA ACUST UNITED AC 2014; 34:815-820. [DOI: 10.1007/s11596-014-1358-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Revised: 11/27/2013] [Indexed: 11/25/2022]
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Fan H, Liu XX, Zhang LJ, Hu H, Tang Q, Duan XY, Zhong M, Shou ZX. Intervention effects of QRZSLXF, a Chinese medicinal herb recipe, on the DOR-β-arrestin1-Bcl2 signal transduction pathway in a rat model of ulcerative colitis. JOURNAL OF ETHNOPHARMACOLOGY 2014; 154:88-97. [PMID: 24637189 DOI: 10.1016/j.jep.2014.03.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2013] [Revised: 03/06/2014] [Accepted: 03/09/2014] [Indexed: 05/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Qingre Zaoshi Liangxue Fang (QRZSLXF) is a Chinese medicinal herb recipe that is commonly prescribed for the treatment of ulcerative colitis. It includes 5 quality assured herbs: Sophora flavescens Aiton., Baphicacanthus cusia (Nees) Bremek., Bletilla striata Rchb.f., Glycyrrhiza uralensis Fisch. and Coptis chinensis Franch. The main phytochemical ingredient of QRZSLXF includes ammothamnine, sophocarpidine, liquiritin, berberine and indirubin. QRZSLXF has been clinically proven for use in the treatment of ulcerative colitis for over twenty years. In the past ten years, research has confirmed the therapeutic effect of QRZSLXF in ulcerative colitis and partially revealed its mechanism of action. Here, we further reveal the therapeutic mechanism of QRZSLXF in ulcerative colitis. To investigate the role of the DOR-β-arrestin1-Bcl-2 signal transduction pathway in ulcerative colitis and to determine the effects of QRZSLXF on this signal transduction pathway. MATERIALS AND METHODS Eighty-four Sprague-Dawley rats were randomly divided into six groups: normal control group, model group, mesalazine group, and QRZSLXF high-dose, medium-dose group and low-dose groups (n=14). Experimental colitis was induced by trinitrobenzenesulfonic acid (TNBS) in each group, except the normal control group. After modeling, bloody stool, mental state and diarrhea were observed and recorded. Two rats were randomly selected from the model groups adfnd sacrificed on day 3 to observe pathological changes in the colon tissue by microscopy. The rats in the QRZSLXF-treated groups received intramuscular injections of different concentrations of QRZSLXF for 15 days. The rats in the mesalazine group were treated with mesalazine solution (0.5 g/kg/day) by gastric lavage for 15 days. The rats in the normal control group and the model group were treated with 3 mL water by gastric lavage for 15 days. On the 16th day, after fasting for 24 h, the remaining rats were sacrificed and their colon tissues were used to detect the mRNA and protein expressions of DOR, β-arrestin1 and Bcl-2 by Real-time PCR and immunohistochemistry, respectively. Histological changes in the colon tissues were also examined. RESULTS AND CONCLUSIONS The expressions of DOR, β-arrestin1 and Bcl-2 were significantly different among the four groups. The expressions of DOR, β-arrestin1 and Bcl-2 protein and mRNA were significantly increased in the model group compared with the other groups (P<0.05). In contrast to the model group, the expressions of DOR, β-arrestin1 and Bcl-2 were significantly decreased in the mesalazine group and the groups that received different doses of QRZSLXF (P<0.05), and there were no statistically significant differences among the mesalazine and QRZSLXF-treated groups (P>0.05). This study indicates that the DOR-beta-arrestin1-Bcl-2 signal transduction pathway may participate in the pathologic course of ulcerative colitis. Moreover, QRZSLXF could attenuate ulcerative colitis by regulating the DOR-β-arrestin1-Bcl-2 signal transduction pathway.
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Affiliation(s)
- Heng Fan
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Xing-xing Liu
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Li-juan Zhang
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Hui Hu
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Qing Tang
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
| | - Xue-yun Duan
- Xueyun Duan, Department of Pharmacy, the Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan 430061, Hubei Province, China
| | - Min Zhong
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Zhe-xing Shou
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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Zheng B, van Bergenhenegouwen J, Overbeek S, van de Kant HJG, Garssen J, Folkerts G, Vos P, Morgan ME, Kraneveld AD. Bifidobacterium breve attenuates murine dextran sodium sulfate-induced colitis and increases regulatory T cell responses. PLoS One 2014; 9:e95441. [PMID: 24787575 PMCID: PMC4008378 DOI: 10.1371/journal.pone.0095441] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 03/27/2014] [Indexed: 12/19/2022] Open
Abstract
While some probiotics have shown beneficial effects on preventing or treating colitis development, others have shown no effects. In this study, we have assessed the immunomodulating effects of two probiotic strains, Lactobacillus rhamnosus (L. rhamnosus) and Bifidobacterium breve (B. breve) on T cell polarization in vitro, using human peripheral blood mononuclear cells (PBMC), and in vivo, using murine dextran sodium sulfate (DSS) colitis model. With respect to the latter, the mRNA expression of T cell subset-associated transcription factors and cytokines in the colon was measured and the T helper type (Th) 17 and regulatory T cell (Treg) subsets were determined in the Peyer's patches. Both L. rhamnosus and B. breve incubations in vitro reduced Th17 and increased Th2 cell subsets in human PBMCs. In addition, B. breve incubation was also able to reduce Th1 and increase Treg cell subsets in contrast to L. rhamnosus. In vivo intervention with B. breve, but not L. rhamnosus, significantly attenuated the severity of DSS-induced colitis. In DSS-treated C57BL/6 mice, intervention with B. breve increased the expression of mRNA encoding for Th2- and Treg-associated cytokines in the distal colon. In addition, intervention with B. breve led to increases of Treg and decreases of Th17 cell subsets in Peyer's patches of DSS-treated mice. B. breve modulates T cell polarization towards Th2 and Treg cell-associated responses in vitro and in vivo. In vivo B. breve intervention ameliorates DSS-induced colitis symptoms and this protective effect may mediated by its effects on the T-cell composition.
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Affiliation(s)
- Bin Zheng
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Science, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Jeroen van Bergenhenegouwen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Science, Faculty of Science, Utrecht University, Utrecht, The Netherlands
- Nutricia Research, Utrecht, The Netherlands
| | - Saskia Overbeek
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Science, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Hendrik J. G. van de Kant
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Science, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Science, Faculty of Science, Utrecht University, Utrecht, The Netherlands
- Nutricia Research, Utrecht, The Netherlands
| | - Gert Folkerts
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Science, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Paul Vos
- Nutricia Research, Utrecht, The Netherlands
| | - Mary E. Morgan
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Science, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Aletta D. Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Science, Faculty of Science, Utrecht University, Utrecht, The Netherlands
- * E-mail:
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Moriasi C, Subramaniam D, Awasthi S, Ramalingam S, Anant S. Prevention of colitis-associated cancer: natural compounds that target the IL-6 soluble receptor. Anticancer Agents Med Chem 2013; 12:1221-38. [PMID: 22583410 DOI: 10.2174/187152012803833080] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2011] [Revised: 01/20/2012] [Accepted: 01/20/2012] [Indexed: 12/17/2022]
Abstract
The risk of developing colorectal cancer increases in patients with inflammatory bowel disease (IBD) and a growing body of evidence shows the critical role of interleukin (IL-6) in this process. IL-6 is both a pro- and anti-inflammatory cytokine whose effects are mediated through activation of STAT3. Recent studies have also demonstrated that IL-6 trans-signaling through its soluble receptor occurs in IBD and cancer. IL-6 trans-signaling therefore is emerging as an attractive approach to diminish the inflammatory signals in conditions of chronic inflammation. The purpose of cancer chemoprevention is to either delay the onset or progression from precancerous lesions. Natural compounds because of their low toxicity render themselves excellent candidates that can be administered over the lifetime of an individual. With the focus of managing IBD over a long time and preventing onset of colitis-associated cancer, we believe that there should be increased research focus on identifying chemopreventive compounds that can render themselves to long term use possibly for the lifetime of predisposed individuals. Here, we review the role of IL-6 signaling in IBD and colitis-associated cancer and underscore the importance of searching for natural compounds that would target the IL-6 trans-signaling pathway as a way to diminish chronic inflammatory conditions in the gastrointestinal tract and possibly hamper the progression to colon cancer. We propose that effective screening and identification of natural chemopreventive compounds that target IL-6 trans-signaling has important implications for the development of optimal strategies against cancer development triggered by inflammation.
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Affiliation(s)
- Cate Moriasi
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Abstract
BACKGROUND Our previous studies have demonstrated that B cells in human inflammatory bowel disease (IBD) are highly activated and produce copious amounts of chemokines. Here, we showed that B cells produce eotaxin-1, a selective chemokine for acute eosinophilia. Increased levels of activated eosinophils have been found in the intestinal mucosa in patients with IBD, but their role(s) and the regulation of their migration patterns remain poorly defined. METHODS To determine how B-cell secretion of eotaxin-1 influences eosinophil activation and migration, we performed immunoepidemiological approaches coupled with in vitro studies. B cells and eosinophils from patients with Crohn's disease and ulcerative colitis were isolated, and responses to Toll-like receptor ligands (TLR) were measured and assessed for the relationship with clinical disease. RESULTS Eotaxin-1 from recirculating B cells, and TLR ligands, regulated eosinophil homing mechanisms in IBD. B cells stimulated with hypo-acylated lipopolysaccharide (LPS) produced copious amounts of eotaxin-1, which influenced eosinophil activation profiles in the bloodstream. We also found that hexa-acylated LPS, such Escherichia coli LPS, directly activated TLR2-expressing and TLR4-expressing eosinophils from patients with IBD to express a different repertoire of mucosal homing receptors, namely CCR9 and CCR10. Whereas B-cell production of eotaxin-1 was correlated with reduced disease activity, eosinophil activation by hexa-acylated LPS was associated with increased disease activity. CONCLUSIONS These results suggest that systemic TLR ligands influence eosinophil migration patterns, both directly and indirectly, through B cells. Our report uncovers unexpected mechanisms of cross talk between certain immune cells that shed new light on IBD immunology.
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Fan H, Zhang LJ, Zhong M, Liu XX, Duan XY, Zuo DM, Tang Q. Intervention effect of Compound Sophorae Flavescentis decoction on DOR-β-arrestin1-Bcl-2 signal transduction pathway in rats with ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2013; 21:647-654. [DOI: 10.11569/wcjd.v21.i8.647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [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
AIM: To explore the intervention effect of Compound Sophorae Flavescentis decoction on the DOR-β-arrestin1-Bcl-2 signal transduction pathway in rats with ulcerative colitis.
METHODS: Eighty-four Sprague-Dawley rats were equally and randomly divided into normal control group, model group, mesalazine group, high-, medium-, and low-dose Compound Sophorae Flavescentis decoction groups. Except for the normal control group, ulcerative colitis was induced with trinitrobenzene sulfonic acid (TNBS) in rats of other groups. After induction of ulcerative colitis, bloody stools, mental state and diarrhea were observed and recorded daily. Two rats in the model group were randomly selected and executed on day 3 for observing pathological changes in the colon tissue. Rats in the mesalazine group and Compound Sophorae Flavescentis decoction groups were lavaged with mesalazine solution and Compound Sophorae Flavescentis decoction for 15 d, while those in the normal control group and model group were given equal volume of distilled water for the same duration. On day 16, the remaining rats were executed to detect histopathological changes in the colon tissue and the mRNA and protein expression of DOR, β-arrestin1 and Bcl-2 in the colon tissue by real-time PCR and immunohistochemistry, respectively.
RESULTS: The mRNA and protein expression of DOR, β-arrestin1 and Bcl-2 differed significantly among each group (P < 0.05). Compared to the normal control group, the mRNA and protein expression of DOR, β-arrestin1 and Bcl-2 protein was significantly increased (24.11 ± 12.61 vs 11.88 ± 5.90, 38.90 ± 5.30 vs 14.34 ± 8.97, 23.57 ± 9.96 vs 9.68 ± 3.94, all P < 0.05) in the colon mucosa in the model group. Compared to the model group, the mRNA and protein expression of DOR, β-arrestin1 and Bcl-2 in the colon mucosa was significantly decreased in the mesalazine group and Compound Sophorae Flavescentis decoction groups; however, the mRNA and protein expression of DOR, β-arrestin1 and Bcl-2 did not differ significantly between the mesalazine group and Compound Sophorae Flavescentis decoction groups.
CONCLUSION: The expression of DOR, β-arrestin1 and Bcl-2 is elevated in ulcerative colitis. The DOR-β-arrestin1-Bcl-2 signal transduction pathway may be involved in the pathogenesis of ulcerative colitis, and Compound Sophorae Flavescentis decoction may have a significant therapeutic effect against ulcerative colitis.
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Zorzi F, Monteleone I, Sarra M, Calabrese E, Marafini I, Cretella M, Sedda S, Biancone L, Pallone F, Monteleone G. Distinct profiles of effector cytokines mark the different phases of Crohn's disease. PLoS One 2013; 8:e54562. [PMID: 23349929 PMCID: PMC3547873 DOI: 10.1371/journal.pone.0054562] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Accepted: 12/12/2012] [Indexed: 12/13/2022] Open
Abstract
Objective Crohn’s Disease (CD)-associated inflammation is supposed to be driven by T helper (Th)1/Th17 cell-derived cytokines, even though there is evidence that the mucosal profile of cytokine may vary with the evolution of the disease. We aimed at comparing the pattern of effector cytokines in early and established lesions of CD. Design Mucosal samples were taken from the neo-terminal ileum of CD patients undergoing ileocolonic resection, with (early lesions) or without post-operative recurrence, and terminal ileum of CD patients with long-standing disease undergoing intestinal resection (established lesions). Inflammatory cell infiltrate was examined by immunofluorescence and cytokine expression was analysed by real-time PCR, flow-cytometry and ELISA. Results Before the appearance of endoscopic lesions, the mucosa of the neo-terminal ileum contained high number of T cells and macrophages, elevated levels of Th1-related cytokines and TNF-α and slightly increased IL-17A expression. Transition from this stage to endoscopic recurrence was marked by abundance of Th1 cytokines, marked increase in IL-17A, and induction of IL-6 and IL-23, two cytokines involved in the control of Th17 cell responses. In samples with established lesions, there was a mixed Th1/Th17 response with no TNF-α induction. Expression of IL-4 and IL-5 was up-regulated in both early and established lesions even though the fraction of IL-4-producing cells was lower than that of cells producing either interferon-γ or IL-17A. Conclusions Distinct mucosal profiles of cytokines are produced during the different phases of CD. A better understanding of the cytokines temporally regulated in CD tissue could help optimize therapeutic interventions in CD.
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Affiliation(s)
- Francesca Zorzi
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Ivan Monteleone
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Massimiliano Sarra
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Emma Calabrese
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Irene Marafini
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Micaela Cretella
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Silvia Sedda
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Livia Biancone
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Francesco Pallone
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
- * E-mail:
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Werner L, Paclik D, Fritz C, Reinhold D, Roggenbuck D, Sturm A. Identification of pancreatic glycoprotein 2 as an endogenous immunomodulator of innate and adaptive immune responses. THE JOURNAL OF IMMUNOLOGY 2012; 189:2774-83. [PMID: 22891285 DOI: 10.4049/jimmunol.1103190] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Pancreatic autoantibodies are Crohn disease-specific serologic markers. The function and immunological role of their recently identified autoantigen, glycoprotein 2 (GP2), are unknown. We therefore investigated the impact of GP2 on modulation of innate and adaptive immune responses to evaluate its potential therapeutic use in mucosal inflammation. Our data indicate a previously unknown function for GP2 as an immunomodulator. GP2 was ubiquitously expressed on cells vital to mucosal immune responses. The expression of GP2 was upregulated on activated human T cells, and it was further influenced by pharmaceutical TNF-α inhibitors. Recombinant GP2 significantly decreased human intestinal epithelial cells, mucosal and peripheral T cell proliferation, apoptosis, and activation, and it distinctly modulated cytokine secretion. Furthermore, intestinal epithelial cells stimulated with GP2 potently attracted T cells. In conclusion, we demonstrate a novel role for GP2 in immune regulation that could provide a platform for new therapeutic interventions in the treatment of Crohn disease.
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Affiliation(s)
- Lael Werner
- Division of Hepatology and Gastroenterology, Department of Medicine, Charité-Campus Virchow Clinic, Medical University of Berlin, 13353 Berlin, Germany
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Jackson LJ, Pheneger JA, Pheneger TJ, Davis G, Wright AD, Robinson JE, Allen S, Munson MC, Carter LL. The role of PIM kinases in human and mouse CD4+ T cell activation and inflammatory bowel disease. Cell Immunol 2012; 272:200-13. [DOI: 10.1016/j.cellimm.2011.10.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Revised: 09/09/2011] [Accepted: 10/17/2011] [Indexed: 01/11/2023]
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van Langenberg DR, Morrison G, Foley A, Buttigieg RJ, Gibson PR. Cytomegalovirus disease, haemophagocytic syndrome, immunosuppression in patients with IBD: 'a cocktail best avoided, not stirred'. J Crohns Colitis 2011; 5:469-72. [PMID: 21939923 DOI: 10.1016/j.crohns.2011.04.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2011] [Revised: 04/14/2011] [Accepted: 04/14/2011] [Indexed: 02/08/2023]
Abstract
We report two cases of cytomegalovirus (CMV) viraemia resulting in severe pneumonitis and associated haemophagocytic syndrome manifesting in patients with inflammatory bowel disease, on stable doses of azathioprine in clinical remission. In both cases, azathioprine was withdrawn at time of hospital presentation and after delays in diagnosis; intravenous ganciclovir was then administered, with resultant rapid improvement of haematological and clinical parameters. Following recovery, immunomodulators were not recommenced given patient aversion and the theoretical risk of CMV reactivation, albeit the evidence for this approach is limited. CMV-related haemophagocytic syndrome and organ dysfunction, in the context of immunomodulator therapy in IBD are rare but life-threatening, and thus requires further investigation and discussion.
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Affiliation(s)
- Daniel R van Langenberg
- Monash University Department of Gastroenterology & Hepatology, Medicine, Box Hill Hospital, Victoria, Australia.
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Platt MP, Soler Z, Metson R, Stankovic KM. Pathways analysis of molecular markers in chronic sinusitis with polyps. Otolaryngol Head Neck Surg 2011; 144:802-8. [PMID: 21493366 DOI: 10.1177/0194599810395091] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE To perform a comprehensive molecular pathways analysis of genes identified through genome-wide expression profiling and the published literature for chronic sinusitis with polyps. STUDY DESIGN Molecular pathways analysis. SETTING Academic medical center. METHODS A molecular pathways analysis of gene biomarkers discovered through hypothesis-driven and high-throughput molecular studies was performed. Genes identified with a PubMed literature search were analyzed with Ingenuity Pathways Analysis software to identify central molecules implicated in the pathogenesis of chronic sinusitis with polyps. The central pathways were then compared with those identified through genome-wide expression profiling of ethmoid polyps. RESULTS A total of 97 molecules were investigated with Ingenuity Pathways Analysis based on 55 studies that evaluated differences in gene expression (39), genetic variation (12), or proteomics (4). The analysis revealed 9 statistically significant molecular networks containing central nodes that included transcription factors, protein kinases, cytokines, and growth factors/receptors. The highest scoring networks implicated nuclear factor kappa-B, tumor necrosis factor, and mitogen-activated protein kinases. The majority of pathways in the literature review analysis overlapped with those identified through a single genome-wide expression study. CONCLUSIONS Chronic sinusitis with polyps is a complex disease with suspected contribution of multiple genetic and environmental factors. The search for causative genes has led to the discovery of numerous candidates. Pathways analysis applied to these candidate genes identified common central molecules that are likely to be key mediators of the disease process. Novel therapies targeting these molecules may be applicable for the treatment of chronic sinusitis with polyps.
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Affiliation(s)
- Michael P Platt
- Department of Otolaryngology-Head and Neck Surgery, Boston University, Boston, Massachusetts 02118, USA.
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Triantafillidis JK, Merikas E, Georgopoulos F. Current and emerging drugs for the treatment of inflammatory bowel disease. Drug Des Devel Ther 2011; 5:185-210. [PMID: 21552489 PMCID: PMC3084301 DOI: 10.2147/dddt.s11290] [Citation(s) in RCA: 202] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Indexed: 12/14/2022] Open
Abstract
During the last decade a large number of biological agents against tumor necrosis factor-α (TNF-α), as well as many biochemical substances and molecules specifically for the medical treatment of patients with inflammatory bowel disease (IBD), have been developed. This enormous progress was a consequence of the significant advances in biotechnology along with the increased knowledge of the underlying pathophysiological mechanisms involved in the pathogenesis of IBD. However, conventional therapies remain the cornerstone of treatment for most patients. During recent years conventional and biologic IBD therapies have been optimized. Newer mesalazine formulations with a reduced pill size and only one dose per day demonstrate similar efficacy to older formulations. New corticosteroids retain the efficacy of older corticosteroids while exhibiting a higher safety profile. The role of antibiotics and probiotics has been further clarified. Significant progress in understanding thiopurine metabolism has improved the effective dose along with adjunctive therapies. Quite a large number of substances and therapies, including biologic agents other than TNF-α inhibitors, unfractionated or low-molecular-weight heparin, omega-3 polyunsaturated fatty acids, microbes and microbial products, leukocytapheresis, and other substances under investigation, could offer important benefits to our patients. In this paper we review the established and emerging therapeutic strategies in patients with Crohn's disease and ulcerative colitis.
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Affiliation(s)
- John K Triantafillidis
- Department of Gastroenterology, Center for Inflammatory Bowel Disease, "Saint Panteleimon" General Hospital, Nicea, Greece.
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Pallone F, Fina D, Caruso R, Monteleone G. Role of IL-21 in inflammatory bowel disease. Expert Rev Clin Immunol 2010; 6:537-41. [PMID: 20594126 DOI: 10.1586/eci.10.44] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
IL-21 was first described as a critical regulator of T- and B-cell functions. More recently, it has become apparent that IL-21 controls the activity of both immune and nonimmune cells and, depending on the timing and context analyzed, it can promote either inflammatory or counter-regulatory effects. IL-21 participates in the immune responses against tumor cells and chronic viral infections, but excessive production of IL-21 has been associated with the development of immune-inflammatory diseases in various organs. In this article, we focus on data supporting the pathogenic role of IL-21 in human inflammatory bowel diseases and discuss preclinical studies that suggest that neutralization of IL-21 in vivo could be a new strategy to counteract the inflammatory bowel disease-related, tissue damaging immune response.
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Affiliation(s)
- Francesco Pallone
- Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
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Abstract
Over the past few decades, inflammation has been recognized as a major risk factor for various human diseases. Acute inflammation is short-term, self-limiting and it's easy for host defenses to return the body to homeostasis. Chronic inflammatory responses are predispose to a pathological progression of chronic illnesses characterized by infiltration of inflammatory cells, excessive production of cytokines, dysregulation of cellular signaling and loss of barrier function. Targeting reduction of chronic inflammation is a beneficial strategy to combat several human diseases. Flavonoids are widely present in the average diet in such foods as fruits and vegetables, and have been demonstrated to exhibit a broad spectrum of biological activities for human health including an anti-inflammatory property. Numerous studies have proposed that flavonoids act through a variety mechanisms to prevent and attenuate inflammatory responses and serve as possible cardioprotective, neuroprotective and chemopreventive agents. In this review, we summarize current knowledge and underlying mechanisms on anti-inflammatory activities of flavonoids and their implicated effects in the development of various chronic inflammatory diseases.
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Affiliation(s)
- Min-Hsiung Pan
- Department of Seafood Science, National Kaohsiung Marine University, No.142, Haijhuan Rd., Nanzih District, Kaohsiung, 81143, Taiwan.
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