The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

Artis, David; Villarino, Alejandro V.; Silverman, Michael A.; He, Weimian; Thornton, Elisabeth M.; Mu, Sharon; Summer, Shamin; Covey, Todd; Huang, Elaine; Yoshida, Hiroki; Koretzky, Gary A.; Goldschmidt, Michael H.; Wu, Gary D.; Sauvage, Fred de; Miller, H. R. P.; Saris, Christiaan J. M.; Scott, Phillip; Hunter, Christopher A.

doi:10.4049/jimmunol.173.9.5626

Cited by 223 publications

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“…A similar phenotype has been shown when IL-27Ra À/À (WSX-1 À/À ) mice were infected with T. muris [36]. These mice developed a strong overproliferative Th2 response, which led to accelerated worm expulsion before day 14 p.i [36]. Recent work has highlighted a role for IL-27 in the suppression of Th2 development of naïve T cells and Th2 cytokine production by polarized Th2 cells by upregulating the expression of the Th1 transcription factor T-bet and simultaneously downregulating GATA3, essential for the Th2 response [37,38].…”

Section: Discussionsupporting

confidence: 73%

“…revealed exaggerated goblet cell and epithelial cell hyperplasia. Again, this phenotype mimics the changes observed in WSX-1 À/À mice [36]. Moreover, T. muris infection of IL-10 À/À gp130 fl/fl CD4-Cre 1 mice caused an influx of macrophages and neutrophils at day 14 p.i., which was in agreement with the augmented inflammation seen in the caecum and with the production of proinflammatory cytokines.…”

supporting

confidence: 71%

supporting

confidence: 58%

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T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

et al. 2009

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Gp130 is the common receptor of the IL-6 family of cytokines and is involved in many biological processes, including acute phase response, inflammation and immune reactions. To investigate the role of gp130 under inflammatory conditions, T-cell-specific conditional gp130 mice were first bred to the IL-10-deficient background and were then infected with the gastrointestinal nematode Trichuris muris. While IL-10 À/À mice were highly susceptible to T. muris, developed a mixed Th1/Th17 response and displayed severe inflammation of the caecum, infection of mice with an additional T-cell-specific deletion of gp130 signalling completely reversed the phenotype. These mice showed an accelerated worm expulsion that was associated with the rapid generation of a strong Th2 immune response and a significant increase in Foxp3-expressing Treg. Therefore, gp130 signalling in T cells regulates a switch between proinflammatory and pathogenic Th1/Th17 cells and regulatory Th2/Treg in vivo. Taken together, the data demonstrate that gp130 signalling in T cells is a positive regulator of inflammatory processes, favouring the Th1/Th17 axis.Key words: Cytokine receptor . Helminthic infection . Inflammation Th1/Th2/Th17 cells Transgenic mice IntroductionThe common receptor gp130 is constitutively expressed on immune and non-immune cells and is used by all members of the IL-6 family, which comprises IL-6, IL-11, leukaemia inhibitory factor, oncostatin M and the recently characterized cytokine IL-27, among others [1,2]. While gp130 acts as the obligate signalling subunit, each cytokine first binds to its specific receptor, which accounts for the difference in activities [3,4]. The lethality of mice with classical disruptions of two gp130 alleles demonstrated that gp130 signalling is important for the development of the nervous and hematopoietic systems [5,6]. Moreover, signals mediated by gp130 regulate multiple other biological functions, including acute phase response, immune reactions and inflammation [7,8]. The receptor is also involved in sustaining the disease state in inflammatory bowel disease, rheumatoid arthritis (RA) or MS [9][10][11]. The Th pathway is composed of, at least, three distinct subsets: Th1 cells produce IFN-g and are involved in the fight against intracellular pathogens. The Th2 immune response with T cells producing IL-4, IL-5 and IL-13 provides immunity to helminths [2]. Th17 cells produce cytokines like IL-17, IL-22 and mediate immunity to extracellular bacteria and fungi, but are also responsible for autoimmunity and inflammation [12,13]. Development of naïve T cells to Th17 cells requires the presence of IL-6, TGF-b1 and the transcription factor RORgt [14][15][16][17]. [20,21]. Since TGF-b1 is a common factor for Treg and Th17 cells, it is possible that a switch from Th17 to Treg exists in vivo in the absence of IL-6 signalling in T cells. The gastrointestinal helminth Trichuris muris is a good model to investigate Th-cell pathways. In common inbred mouse strains (BALB/c, C57BL/6), infection with T. muris is...

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Section: Discussionsupporting

confidence: 73%

supporting

confidence: 71%

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T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

et al. 2009

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“…To this end, NOD/SCIDIl2rg À/À (NSG) mice were injected with B-ALL cells obtained from BM pediatric patients and treated with IL-27 or phosphate buffered saline (PBS). On the basis of previous studies, 17 TICs were identified as CD133 þ CD19 À cells, as this population (1) was the only one within the whole B-ALL tumor that could self-renew to engraft serial SCID/NOD recipients, 17 (2) differentiates in vivo to produce leukemias with similar immunophenotypic and karyotypic features similar to those detected in primary tumor samples 17 and (3) was more resistant to treatment with dexamethasone and vincristine, 17 key components in childhood ALL therapy, than the bulk leukemia population.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4][5][6] The IL-27R contains the unique receptor subunit WSX-1, paired with the gp130 chain; both chains are necessary for IL-27 signaling. 7,8 IL-27 exerts antitumor activity in different tumors through indirect 5,9-11 and direct mechanisms.…”

Section: Introductionmentioning

confidence: 99%