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 CD4+CD25+Foxp3+ Treg population increased. In vitro studies revealed that IL-27 inhibited IL-17 production in murine CD4+ T cells, and the effect was associated with retinoic acid-related orphan receptor γT and signal transducer and activator of transcription 3 inhibition. 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-4+ (cytotoxic T-lymphocyte antigen 4), PD-1+ (programmed cell death protein 1) and GITR+ (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 CD4+ 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.
Highlights
Interleukin (IL)-27 is a member of a heterodimeric cytokine produced by antigen-presenting cells (APCs), including monocytes and dendritic cells
We found that IL-27 acts as a reciprocal regulator of the T helper 17 (Th17) and Treg populations in CD4 þ cells isolated from healthy human peripheral blood mononuclear cells (PBMCs), as well as from humans with rheumatoid arthritis (RA) PBMCs
Sorted CD4 þ CD25 þ cells were cocultured with T cells and irradiated APC (7500 cGy) at a 0.2:1:1 ratio in the presence of RESULTS The regulatory effect of IL-27 on the Th17/Treg population during collagen-induced arthritis (CIA) development To determine whether IL-27 modulates disease severity in vivo, IL-27-Fc was administered by hydrodynamic injection into mice 8 days after CII immunization
Summary
Interleukin (IL)-27 is a member of a heterodimeric cytokine produced by antigen-presenting cells (APCs), including monocytes and dendritic cells. It belongs to the IL-12 cytokine family, which includes IL-23 and IL-35.1 IL-27 is composed of the Epstein–Barr virus-induced gene 3 (EBI3) and p28 subunits, and has been demonstrated to have a pivotal role as both a pro- and anti-inflammatory cytokine.[2] A recent report by. Wojno et al.[3] showed that IL-27 transgenic mice exhibited a systemic inflammatory condition accompanied by an increased percentage of activated T cells and an elevated interferon (IFN)-g level. Republic of Korea 5These authors contributed to this work.
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