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Interleukin-27 receptor-deficient mice develop exacerbated inflammatory arthritis associated with heightened T- and B- cell responses [Abstract]

Jones, Gareth Wyn, Williams, Anwen Sian ORCID:, Nowell, Mari Ann, Jenkins, Brian J. and Jones, Simon Arnett ORCID: 2011. Interleukin-27 receptor-deficient mice develop exacerbated inflammatory arthritis associated with heightened T- and B- cell responses [Abstract]. Arthritis and Rheumatism 63 (s10) , S978-S978. 10.1002/art.33310

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Background/Purpose: Cytokine control of the adaptive immune response is a central process in the development of inflammatory diseases. T helper cells that produce interleukin-17 (IL-17; Th17 cells) have recently been identified as a distinct T cell subset implicated in a number of autoimmune diseases including rheumatoid arthritis (RA). As such, targeting of the inflammatory pathways that promote Th17 cell responses are currently of interest for developing new therapies to treat RA. The interleukin (IL)-6 family of cytokines share the ubiquitously expressed glycoprotein 130 (gp130) receptor for activation of intracellular signaling pathways and members of this family, most notably IL-6 and IL-27, have emerged as key regulators of the Th17 cell response. Through differential activation of signaling transducers and activators of transcription (STAT)1 and STAT3, IL-6 and IL-27 have opposing outcomes on the generation of Th17 cells. IL-6/STAT3 signaling promotes the differentiation of Th17 cells from naïve T helper cells while IL-27 via STAT1 counteracts this IL-6-driven process. Accordingly, IL-6 receptor-deficient (IL-6R-/-) mice are protected from inflammatory arthritis, display no T cell infiltrates in the synovium and have an impaired Th17 cell response. Studies in IL-27R-/- mice have highlighted an anti-inflammatory role for IL-27 in inflammatory diseases. However, the mechanisms linking IL-27 to arthritis progression remain unclear. Methods: Experimental inflammatory arthritis was induced in wild type (WT) mice and IL-27R-/- mice. Disease severity was assessed through measurement of joint swelling, histological analysis of joint sections and x-ray. Flow cytometry, immunohistochemical and immunological assays were used to monitor the peripheral immune response and the cellular response within the synovium. To support in vivo studies, in vitro approaches investigated T helper cell responses to IL-27. Results: IL-27R-/- mice developed exacerbated inflammatory arthritis, displaying increased synovial infiltrates and bone erosions compared to WT mice. IL-27R-/- mice also displayed increased peripheral Th17 cell responses and higher serum IL-17 levels. Surprisingly, these mice also had heightened B cell responses associated with an increase in antigen specific serum IgG levels. Immunohistochemical analysis of synovial infiltrates revealed increased activation of STAT3 was associated with disease exacerbation, further confirming a damaging role for local STAT3 activation in arthritis progression. Conclusion: Experimental inflammatory arthritis provides a valuable model for understanding the role of cytokines in inflammation-induced disease pathology. In this regard, IL-27R-/- mice develop exacerbated joint disease, demonstrating a protective role for IL-27 in inflammatory arthritis. This anti-inflammatory effect of IL-27 is attributed to regulation of T- and B- cell responses and modulation of STAT1/3 activation. Excessive activation of STAT3 within the joint contributes to inflammation-induced joint pathology and modulating the STAT1/3 axis may provide a potential therapeutic approach. In this regard, targeting of the IL-27 signaling pathway is currently being explored.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine
Additional Information: Abstracts of the American College of Rheumatology/Association of Rheumatology Health Professionals Annual Scientific Meeting Chicago, Illinois November 4-9, 2011.
Publisher: Wiley-Blackwell
ISSN: 0004-3591
Last Modified: 09 Nov 2022 08:45

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