In vivo action of IL-27: reciprocal regulation of Th17 and Treg cells in collagen-induced arthritis

다국어 초록 (Multilingual Abstract)

Interleukin (IL)-27 is a novel cytokine of the IL-6/IL-12 family that has been reported to be involved in the pathogenesis of autoimmune diseases and has a pivotal role as both a pro- and anti-inflammatory cytokine. We investigated the in vivo effects of IL-27 on arthritis severity in a murine collagen-induced arthritis (CIA) model and its mechanism of action regarding control of regulatory T (Tregs) and IL-17-producing T helper 17 (Th17) cells. IL-27-Fc-treated CIA mice showed a lower severity of arthritis. IL-17 expression in the spleens was significantly decreased in IL-27-Fc-treated CIA mice compared with that in the CIA model. The Th17 population was decreased in the spleens of IL-27-Fc-treated CIA mice, whereas the CD4þCD25þFoxp3þTreg population increased. In vitro studies revealed that IL-27 inhibited IL-17 production in murine CD4þ T cells, and the effect was associated with retinoic acid-related orphan receptor cT and signal transducer and activator of transcription 3inhibition. In contrast, fluorescein isothiocyanate-labeled forkhead box P3 (Foxp3) and IL-10 were profoundly augmented by IL-27 treatment. Regarding the suppressive capacity of Treg cells, the proportions of CTLA-4þ (cytotoxic T-lymphocyte antigen 4), PD-1þ (programmed cell death protein 1) and GITRþ (glucocorticoid-induced tumor necrosis factor receptor) Tregs increased in the spleens of IL-27-Fc-treated CIA mice. Furthermore, in vitro differentiated Treg cells with IL-27 exerted a more suppressive capacity on T-cell proliferation. We found that IL-27 acts as a reciprocal regulator of the Th17 and Treg populations in CD4þ cells isolated from healthy human peripheral blood mononuclear cells (PBMCs), as well as from humans with rheumatoid arthritis (RA) PBMCs. Our study suggests that IL-27 has the potential to ameliorate overwhelming inflammation in patients with RA through a reciprocal regulation of Th17 and Treg cells.

참고문헌 (Reference)

1 Villarino AV, "Understanding the pro- and antiinflammatory properties of IL-27" 173 : 715-720, 2004

2 Ha SJ, "Therapeutic effect of DNA vaccines combined with chemotherapy in a latent infectionmodel after aerosol infection of mice with Mycobacterium tuberculosis" 10 : 1592-1599, 2003

3 Lubberts E, "The role of T-cell interleukin- 17 in conducting destructive arthritis: lessons from animal models" 7 : 29-37, 2005

4 Manel N, "The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat" 9 : 641-649, 2008

5 Hall AO, "The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology" 37 : 511-523, 2012

6 Valencia X, "TNF downmodulates the function of human CD4þCD25hi T-regulatory cells" 108 : 253-261, 2006

7 Acosta-Rodriguez EV, "Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells" 8 : 639-646, 2007

8 Goldberg R, "Suppression of ongoing adjuvant-induced arthritis by neutralizing the function of the p28 subunit of IL-27" 173 : 1171-1178, 2004

9 Hirota K, "Sugimoto N et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model" 204 : 2803-2812, 2007

10 Shimizu J, "Stimulation of CD25(þ)CD4(þ) regulatory T cells through GITR breaks immunological self-tolerance" 3 : 135-142, 2002

11 Francisco LM, "PD-L1 regulates the development, maintenance, and function of induced regulatory T cells" 206 : 3015-3029, 2009

12 Bodhankar S, "Oestrogen treatment of experimental autoimmune encephalomyelitis requires 17beta-oestradiol-receptor- positive B cells that up-regulate PD-1 on CD4þ Foxp3þ regulatory T cells" 137 : 282-293, 2012

13 Schaer DA, "Modulation of GITR for cancer immunotherapy" 24 : 217-224, 2012

14 Pickens SR, "Local expression of interleukin-27 ameliorates collageninduced arthritis" 63 : 2289-2298, 2011

15 Genovese MC, "LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study" 62 : 929-939, 2010

16 Cao D, "Isolation and functional characterization of regulatory CD25brightCD4þ T cells from the target organ of patients with rheumatoid arthritis" 33 : 215-223, 2003

17 Park JS, "Interleukin-27 suppresses osteoclastogenesis via induction of interferon-gamma" 137 : 326-335, 2012

18 Park JS, "Interleukin-27 suppresses osteoclastogenesis via induction of interferon-gamma" 137 : 326-335, 2012

19 Stumhofer JS, "Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system" 7 : 937-945, 2006

20 Batten M, "Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells" 7 : 929-936, 2006

21 Niedbala W, "Interleukin 27 attenuates collagen-induced arthritis" 67 : 1474-1479, 2008

22 Harrington LE, "Interleukin 17-producing CD4þ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages" 6 : 1123-1132, 2005

23 Pflanz S, "IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(þ) T cells" 16 : 779-790, 2002

24 Villarino AV, "IL-27 limits IL-2 production during Th1 differentiation" 176 : 237-247, 2006

25 Shibata S, "IL-27 activates Th1-mediated responses in imiquimod-induced psoriasis-like skin lesions" 133 : 479-488, 2013

26 Langrish CL, "IL-23 drives a pathogenic T cell population that induces autoimmune inflammation" 201 : 233-240, 2005

27 Yang L, "IL-21 and TGF-beta are required for differentiation of human T(H)17 cells" 454 : 350-352, 2008

28 Lubberts E, "IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis?" 41 : 84-91, 2008

29 Nakae S, "IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist" 100 : 5986-5990, 2003

30 Lubberts E, "IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis" 167 : 1004-1013, 2001

31 Partsch G, "Highly increased levels of tumor necrosis factor-alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid" 24 : 518-523, 1997

32 Bettan M, "High-level protein secretion into blood circulation after electric pulsemediated gene transfer into skeletal muscle" 2 : 204-210, 2000

33 Park MK, "Grape seed proanthocyanidin extract (GSPE) differentially regulates Foxp3(þ) regulatory and IL-17(þ) pathogenic T cell in autoimmune arthritis" 135 : 50-58, 2011

34 Waldburger JM, "Garden of therapeutic delights: new targets in rheumatic diseases" 11 : 206-, 2009

35 Wong CK, "Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis" 12 : R129-, 2010

36 Tang Q, "Distinct roles of CTLA-4 and TGF-beta in CD4þCD25þ regulatory T cell function" 34 : 2996-3005, 2004

37 Nishimura H, "Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor" 11 : 141-151, 1999

38 Flores-Borja F, "Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis" 105 : 19396-19401, 2008

39 Read S, "Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(þ)CD4(þ) regulatory cells that control intestinal inflammation" 192 : 295-302, 2000

40 Steiner G, "Cytokine production by synovial T cells in rheumatoid arthritis" 38 : 202-213, 1999

41 Takeda A, "Cutting edge: role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment" 170 : 4886-4890, 2003

42 Ehrenstein MR, "Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy" 200 : 277-285, 2004

43 Wing K, "CTLA-4 control over Foxp3þ regulatory T cell function" 322 : 271-275, 2008

44 Mottonen M, "CD4þ CD25þ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis" 140 : 360-367, 2005

45 Morgan ME, "CD25þ cell depletion hastens the onset of severe disease in collagen-induced arthritis" 48 : 1452-1460, 2003

46 Nadkarni S, "Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta" 204 : 33-39, 2007

47 Sakaguchi S, "Animal models of autoimmunity and their relevance to human diseases" 12 : 684-690, 2000

48 Hu Y, "Advances in research on animal models of rheumatoid arthritis" 32 : 161-165, 2012

49 Zheng XX, "Administration of noncytolytic IL-10/Fc in murine models of lipopolysaccharide- induced septic shock and allogeneic islet transplantation" 154 : 5590-5600, 1995

50 Wojno ED, "A role for IL-27 in limiting T regulatory cell populations" 187 : 266-273, 2011

51 Park H, "A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17" 6 : 1133-1141, 2005