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 gammaT 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.