Interleukin-27-Mediated Suppression of Human Th17 Cells Is Associated with Activation of STAT1 and Suppressor of Cytokine Signaling Protein 1

Abstract

Accumulating evidence indicates that interleukin (IL)-27, a member of the IL-12 family of cytokines, antagonizes pathological Th17 effector cell responses. Relatively little is known about the cytokines that regulate human Th17 cells. In this study, we investigated the effect of IL-27 on the differentiation of human Th17 cells and on committed memory Th17 cells. We demonstrate that IL-27 suppresses the development of human Th17 cells by downregulating retinoid orphan nuclear receptor C expression and that this inhibition is associated with the induction of the intracellular signaling factors STAT1 and induction of the suppressor of cytokine signaling protein 1. The IL-27-mediated inhibition of IL-17 is independent of IL-10. We show that IL-27 inhibits differentiation of naïve T cells into IL-17 þ T cells under different Th17 polarizing conditions. IL-27 suppresses other Th17 subset cytokines such as IL-22 and IL-21 but not tumor necrosis factor-a. Moreover, we also show that IL-27 inhibits IL-17 production by committed Th17 memory cells, which is independent of IL-10. These studies show that IL-27 negatively regulates both the developing and committed human Th17 responses and therefore may be a promising therapeutic approach in the treatment of Th17-mediated diseases.

Interleukin 27 (IL-27) Alleviates Bone Loss in Estrogen-deficient Conditions by Induction of Early Growth Response-2 Gene

“…Additionally, decreased ROR␥t and increased transcript levels were observed in CD4 ϩ T cells harvested from IL-27-treated Ovx animals. Studies have shown that SOCS-3 participates in IL-27-mediated suppression of Th17 cell production (25); therefore, levels of SOCS-3 in Ovx and IL-27-treated Ovx mice were determined. Reduced SOCS-3 levels were found in Ovx mice, whereas IL-27 treatment regained the SOCS-3 mRNA levels comparable with the sham control group.…”

“…Thus, IL-27 mitigates Ovx-induced Th17 generation and differentiation. A study by Liu and Rohowsky-Kochan (25) suggests that SOCS-3 (suppressor of cytokine signaling) participates in IL-27-mediated suppression of Th17 cell production; hence levels of SOCS-3 in Ovx and IL-27-treated Ovx mice were determined. It was observed that Ovx led to robust down-regulation of SOCS-3, whereas treatment with IL-27 brought back the mRNA levels to sham control ( Fig.…”

C-type lectin receptors in the control of T helper cell differentiation

“…2). The recognition of Candida albicans β-glucans by dectin 1 triggers SYK-dependent interferon-regulatory factor 5 (IRF5) activation and the subsequent expression of interferon-β (IFNβ) 38 , which results in the downregulation of IL-1β expression and the induction of IL-27 that together downregulate T H 17 cell responses 39,40 .…”

Interleukin-17A as a Biomarker for Bovine Tuberculosis

“…Infection also elicited IL-17F, IL-22, and IL-27 responses. IL-27 is a known inhibitor of Th17 responses in mice and humans (51,52); however, both IL-27 (44) and IL-17 (41,43) are associated with active disease in M. tuberculosis infections in humans. Thus, perhaps it is not too surprising that IL-27 and Th17 cytokine responses followed similar kinetics.…”