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Susceptibility to Experimental Arthritis IL-27 Induces a Th1 Immune IL-27 Induces a Th1 Immune Response and Susceptibility to Experimental Arthritis Yanxia Cao, Paul D. Doodes, Tibor T. Glant and Alison Finnegan This information is current as of September 28, 2021. J Immunol 2008; 180:922-930; ; doi: 10.4049/jimmunol.180.2.922 http://www.jimmunol.org/content/180/2/922 Downloaded from References This article cites 49 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/180/2/922.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-27 Induces a Th1 Immune Response and Susceptibility to Experimental Arthritis1 Yanxia Cao,† Paul D. Doodes,* Tibor T. Glant,‡ and Alison Finnegan2*† IL-27 is the newest member of the cytokine family comprised of IL-12 and IL-23. IL-27 was originally described as a cytokine that along with IL-12 induces the differentiation of naive precursor T cells into Th1 effector cells. This activity has been called into question based on evidence in infectious disease and autoimmune models in which IL-27 is not absolutely required for the generation of IFN-␥, and IL-27 plays a regulatory role in controlling inflammation. We have previously reported in proteoglycan- induced arthritis (PGIA), a model of rheumatoid arthritis, that severe arthritis is dependent on the production of IFN-␥. In this study, we report that IL-27 was expressed in spleen and joint tissues of arthritic mice. We determined the involvement of IL-27 in PGIA by assessing the progression of arthritis in IL-27R؊/؊ mice. Development of arthritis in IL-27R؊/؊ mice was delayed and ؉/؉ severity reduced in comparison with IL-27R littermate controls. Histology confirmed a reduction in joint cellularity, cartilage Downloaded from destruction, and bone erosion. Diminished arthritis was associated with fewer T cells producing IFN-␥ and decreased IFN-␥ secretion overtime. Moreover, the frequency of IL-4- and IL-17-expressing T cells and the production of IL-4 and IL-17 were similar in IL-27R؊/؊ mice and controls. Our results indicate that IL-27 is critically involved in the induction of inflammation in PGIA. IL-27 functions by inducing the differentiation of IFN-␥-producing T cells in vivo that are essential for the development of arthritis. The Journal of Immunology, 2008, 180: 922–930. http://www.jimmunol.org/ nterleukin-27 is a heterodimeric cytokine composed of EBV- 27R-deficient mice display enhanced accumulation of Th1 effector induced gene 3 (EBI3)3 and p28 that signals through a re- (11) cells and increased production of IFN-␥ during infection with I ceptor complex composed of the unique IL-27R␣ (IL-27R) Toxoplasma gondi, Trypansoma cruzii,orMyobacterium tubercu- (also called WSX-1 or T cell cytokine receptor (TCCR)) and losis (12, 13). Similarly, in Con A-induced hepatitis, experimental gp130. IL-27 belongs to a family of structurally related ligands that autoimmune encephalomyelitis (EAE), and chronic T. gondii in- include IL-12, IL-23, and IL-6 (1–4). IL-27R is expressed on naive fection, absence of IL-27R exacerbates disease and the production T cells, NK cells, monocytes, mast cells, and activated B cells and of IL-17 by T cells (14–16). IL-27 inhibitory activity is related to dendritic cells, whereas IL-27 is produced mainly by activated its ability to suppress several different cytokines. IL-27 has been macrophages and dendritic cells (1–3, 5–7). Initial studies focused shown to reduce IL-4 production, which in turn may exacerbate by guest on September 28, 2021 on the influence of IL-27 on Th1 responses because of the struc- Th1 responses (17–19). Studies also suggest that IL-27 can limit tural homology between IL-27 and IL-12. These studies showed CD4ϩ T cell IL-2 and IL-17 production (14, 15, 20, 21). Thus, the that similar to IL-12, IL-27 promotes T cell proliferation and the marked suppressor activity of IL-27 in these particular systems production of IFN-␥ by naive T cells (1). Consistent with in vitro may overshadow the role of IL-27 in Th1 differentiation. studies, IL-27R-deficient mice produce less IFN-␥ in vivo and are Proteoglycan (PG)-induced arthritis (PGIA) is a murine more susceptible to infection with Listeria monocytogenes (2). model of rheumatoid arthritis (22). In PGIA, immunization of Moreover, both IL-27 and IL-12 are capable of inducing T-bet, female BALB/c mice with proteoglycan induces a population of IFN-␥, and IL-12R␤2 expression in naive T cells in a STAT1- CD4ϩ T cells to produce IFN-␥ (23). IFN-␥ is a dominant cy- dependent manner (6, 8–10). However, subsequent studies indi- tokine regulating PGIA, as illustrated by the observation that cate that IL-27 can limit several Th1-type immune responses. IL- arthritis onset and severity are reduced under conditions in which IFN-␥ is neutralized with Abs or in mice lacking IFN-␥ (24). Interestingly, PGIA differs from several other autoimmune *Department of Immunology/Microbiology and †Department of Internal Medicine, disease models, specifically collagen-induced arthritis (CIA) Section of Rheumatology, and ‡Department of Orthopedic Surgery, Rush University and “new” EAE, in which autoimmune disease is exacerbated in Medical Center, Chicago, IL 60612 susceptible strains lacking either IFN-␥ or the IFN-␥ receptor Received for publication September 12, 2007. Accepted for publication November 12, 2007. (25–27). Moreover, STAT4-deficient mice are similarly resis- tant to PGIA, indicating that IL-12R signaling is an important The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance component of disease development (24). We were therefore in- with 18 U.S.C. Section 1734 solely to indicate this fact. terested in determining whether IL-27 functioned to enhance or 1 This research was supported by National Institutes of Health Grant AR45652 (to suppress the Th1-mediated response in PGIA. Our results dem- A.F. and T.T.G.). onstrated that IL-27R-deficient mice were more resistant to in- 2 Address correspondence and reprint requests to Dr. Alison Finnegan, Department of duction of arthritis than wild-type mice. The loss of IL-27R Medicine, Section of Rheumatology, Rush University Medical Center, 1735 West ␥ Harrison Avenue, Chicago, IL 60612. E-mail address: [email protected] signaling resulted in reduced IFN- production and fewer IFN- ␥ ϩ 3 Abbreviations used in this paper: EBI3, EBV-induced gene 3; CIA, collagen-in- -producing CD4 T cells. Moreover, production of IL-2, IL-4, duced arthritis; Ct, cycle threshold; EAE, experimental autoimmune encephalomy- and IL-17 was not significantly altered in the absence of IL-27 elitis; PGIA, proteoglycan-induced arthritis; Tg, transgenic; PG, proteoglycan; signaling. These studies demonstrate that IL-27 expression is an TCCR, T cell cytokine receptor. important cytokine for driving the IFN-␥ response that is crit- Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 ical for the induction of PGIA. www.jimmunol.org The Journal of Immunology 923 FIGURE 1. Activation of primary PG-specific T cells by IL-27. CD4ϩ T cells from PG-specific TCR Tg mice were cultured with naive irradiated spleen cells in presence or absence of PG (5 ␮g/ml), IL-27 (1 ng/ml), or the combination of PG and IL-27. T cell proliferation (A) was measured on day 4 by the incorporation of [3H]thymidine. T cell IFN-␥ production (B) was measured in day 4 supernatants by ELISA. T cell IFN-␥ mRNA transcripts (C) were measured at4hbyPCR. T cell RNA from nonimmune mice was used to calculate the relative fold increase in IFN-␥ RNA. Values are the mean Ϯ SD .p Ͻ 0.05. Data are representative of two separate experiments ,ء .of quadruplicate cultures Downloaded from Materials and Methods nology Associates). Data represent the mean Ϯ SEM of Abs from six to Mice eight individual mice. T cell cytokine receptor-deficient mice (designated in this study as IL- Assessment of T cell activation by proliferation 27RϪ/Ϫ) were provided by F. de Sauvage (Genentech, South San Fran- cisco, CA) (2). IL-27RϪ/Ϫ mice were backcrossed to BALB/c (Charles CD4ϩ (2.5 ϫ 105 cells/well) purified by AutoMACS selection (Miltenyi http://www.jimmunol.org/ River Laboratories) for seven generations and then intercrossed to obtained Biotec) were stimulated with PG (10 ␮g/ml) and irradiated (2500 rad) IL-27Rϩ/ϩ and IL-27RϪ/Ϫ littermates. Female BALB/c age-matched IL- spleen cells (2.5 ϫ 105 cells/well) from naive IL-27Rϩ/ϩ mice. Cells were 27Rϩ/ϩ and IL-27RϪ/Ϫ littermates 12–14 wk of age were used in all ex- cultured in quadruplicate in 96-well Falcon plates (Fisher Scientific) in periments. TCR transgenic (Tg) mice expressing a TCR specific for a dom- RPMI 1640 medium containing 10% FCS, 100 ␮g/ml penicillin, 100 inant epitope of human PG were used to test primary responses to IL-27 ␮g/ml streptomycin, and 2 mM L-glutamine (complete medium).
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