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IL-27 promotes T cell–dependent colitis through multiple mechanisms

Interleukin-27 (IL-27) is a cytokine known to have both proinflammatory and immunoregulatory functions. The latter appear to dominate in vivo, where IL-27 suppresses TH17 responses and promotes the differentiation of Tr1 cells expressing interferon-γ and IL-10 and lacking forkhead box P3 (Foxp3). Ac...

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Autores principales: Cox, Jennifer H., Kljavin, Noelyn M., Ramamoorthi, Nandhini, Diehl, Lauri, Batten, Marcel, Ghilardi, Nico
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023127/
https://www.ncbi.nlm.nih.gov/pubmed/21173106
http://dx.doi.org/10.1084/jem.20100410
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author Cox, Jennifer H.
Kljavin, Noelyn M.
Ramamoorthi, Nandhini
Diehl, Lauri
Batten, Marcel
Ghilardi, Nico
author_facet Cox, Jennifer H.
Kljavin, Noelyn M.
Ramamoorthi, Nandhini
Diehl, Lauri
Batten, Marcel
Ghilardi, Nico
author_sort Cox, Jennifer H.
collection PubMed
description Interleukin-27 (IL-27) is a cytokine known to have both proinflammatory and immunoregulatory functions. The latter appear to dominate in vivo, where IL-27 suppresses TH17 responses and promotes the differentiation of Tr1 cells expressing interferon-γ and IL-10 and lacking forkhead box P3 (Foxp3). Accordingly, IL-27 receptor α (Il27ra)–deficient mice suffer from exacerbated immune pathology when infected with various parasites or challenged with autoantigens. Because the role of IL-27 in human and experimental mouse colitis is controversial, we studied the consequences of Il27ra deletion in the mouse T cell transfer model of colitis and unexpectedly discovered a proinflammatory role of IL-27. Absence of Il27ra on transferred T cells resulted in diminished weight loss and reduced colonic inflammation. A greater fraction of transferred T cells assumed a Foxp3(+) phenotype in the absence of Il27ra, suggesting that IL-27 functions to restrain regulatory T cell (T(reg)) development. Indeed, IL-27 suppressed Foxp3 induction in vitro and in an ovalbumin-dependent tolerization model in vivo. Furthermore, effector cell proliferation and IFN-γ production were reduced in the absence of Il27ra. Collectively, we describe a proinflammatory role of IL-27 in T cell–dependent intestinal inflammation and provide a rationale for targeting this cytokine in pathological situations that result from a breakdown in peripheral immune tolerance.
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spelling pubmed-30231272011-07-17 IL-27 promotes T cell–dependent colitis through multiple mechanisms Cox, Jennifer H. Kljavin, Noelyn M. Ramamoorthi, Nandhini Diehl, Lauri Batten, Marcel Ghilardi, Nico J Exp Med Article Interleukin-27 (IL-27) is a cytokine known to have both proinflammatory and immunoregulatory functions. The latter appear to dominate in vivo, where IL-27 suppresses TH17 responses and promotes the differentiation of Tr1 cells expressing interferon-γ and IL-10 and lacking forkhead box P3 (Foxp3). Accordingly, IL-27 receptor α (Il27ra)–deficient mice suffer from exacerbated immune pathology when infected with various parasites or challenged with autoantigens. Because the role of IL-27 in human and experimental mouse colitis is controversial, we studied the consequences of Il27ra deletion in the mouse T cell transfer model of colitis and unexpectedly discovered a proinflammatory role of IL-27. Absence of Il27ra on transferred T cells resulted in diminished weight loss and reduced colonic inflammation. A greater fraction of transferred T cells assumed a Foxp3(+) phenotype in the absence of Il27ra, suggesting that IL-27 functions to restrain regulatory T cell (T(reg)) development. Indeed, IL-27 suppressed Foxp3 induction in vitro and in an ovalbumin-dependent tolerization model in vivo. Furthermore, effector cell proliferation and IFN-γ production were reduced in the absence of Il27ra. Collectively, we describe a proinflammatory role of IL-27 in T cell–dependent intestinal inflammation and provide a rationale for targeting this cytokine in pathological situations that result from a breakdown in peripheral immune tolerance. The Rockefeller University Press 2011-01-17 /pmc/articles/PMC3023127/ /pubmed/21173106 http://dx.doi.org/10.1084/jem.20100410 Text en © 2011 Cox et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Cox, Jennifer H.
Kljavin, Noelyn M.
Ramamoorthi, Nandhini
Diehl, Lauri
Batten, Marcel
Ghilardi, Nico
IL-27 promotes T cell–dependent colitis through multiple mechanisms
title IL-27 promotes T cell–dependent colitis through multiple mechanisms
title_full IL-27 promotes T cell–dependent colitis through multiple mechanisms
title_fullStr IL-27 promotes T cell–dependent colitis through multiple mechanisms
title_full_unstemmed IL-27 promotes T cell–dependent colitis through multiple mechanisms
title_short IL-27 promotes T cell–dependent colitis through multiple mechanisms
title_sort il-27 promotes t cell–dependent colitis through multiple mechanisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023127/
https://www.ncbi.nlm.nih.gov/pubmed/21173106
http://dx.doi.org/10.1084/jem.20100410
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