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

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.

Cytokine measurements in Brazilian postmenopausal osteoporosis patients reveal high levels of IL-8

“…By contrast, a recent study found that IL-27 could be beneficial by inhibiting osteoclastogenesis [19]. This study corroborates the findings of other ones that consider IL-27 to be an anti-inflammatory factor [20] and a possible positive inflammatory regulator in arthritis [21], multiple sclerosis [22], and even cancer [23]. IL-27 is a cytokine that probably acts in the regulation of bone homeostasis.…”

Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17–Neutrophil Response

“…Moreover, neutrophils were also reduced after anti-IL-17 treatment, confirming the role of IL-17 in neutrophil recruitment to infected organs in parallel to induction of NO production by macrophages, as previously shown by our group. The regulatory role of IL-27 on IL-17 response has been demonstrated under autoimmune inflammatory conditions, such as in experimental autoimmune encephalomyelitis (12) as well as in collagen-induced arthritis (31). Here, we suggest that IL-27 plays a major role as an important regulatory cytokine implicated in infectious disease.…”

Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity

“…and PD-1 [133], or LAG3 (on human Treg) [134] on their cell surface. Jeon et al [135], have reported that B. breve activates intestinal CD103 + DCs to produce IL-10 and IL-27 via the TLR2/MyD88 pathway thereby inducing IL-10-producing Tr1 cells in the large intestine and thus prevents intestinal inflammation.…”