Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells

Abstract

Inflammatory bowel disease (IBD) represents a group of chronic inflammatory diseases characterized by inflammation and relapsing gastrointestinal disorders. Recent studies have shown that Th17 cells, which are well known as key mediators of chronic inflammation, have a pivotal role in onset and development of IBD in humans and mice, alike. In recent years, it has been reported that IL-27, which is an IL-12-related heterodimeric cytokine consisting of EBI3 and p28 subunits, act directly on naive T cells to suppress the differentiation of Th17 cells. However, effects of exogenous IL-27 on the IBD are not well elucidated. To clarify the suppressive effect of IL-27 treatment on IBD, we applied the flexible linking method to EBI3 and p28 subunits and generated a single-chain human IL-27 (scIL-27). scIL-27 inhibited xenogenic mouse Th17 cell differentiation in vitro, indicating that scIL-27 also acts in mouse immune systems. In a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse acute colitis model, subcutaneous scIL-27 treatment significantly improved the colon length, extent of necrosis, and ulceration and thickened epithelium and several pathological scores in a dose-dependent manner. scIL-27 clearly suppressed several inflammatory cytokines, including IL-17, in inflamed colon, except for anti-inflammatory cytokine IL-10. The mesenteric lymph node cells from scIL-27-treated mice also exhibited a reduced inflammatory response and, furthermore, a lower population of Th17 cells than those of PBS-treated mice. Finally, we showed the therapeutic efficacy of scIL-27 on TNBS-induced colitis even after active colitis was established. These results suggest new possible therapeutic approaches for IBD, including disorders such as Crohn's disease and ulcerative colitis.

Elevated interleukin-27 enhances the polarization of Th1/Tc1 cells and the production of proinflammatory cytokines in primary immune thrombocytopenia

“…Because the differentiation of Th1 can antagonize the development of other types of Th cells, we speculate that the inhibitory effect on Gata-3 and ROR-␥t is not caused by IL-27, but by increased IFN-␥. Nevertheless, in PBMCs of normal controls, as reported by Sasaoka et al [37], IL-27 can inhibit the differentiation of Th17 cells. This difference between ITP patients and normal controls is attributed to the abnormal Th17 differentiation in ITP patients, but the exact mechanism requires further study.…”

A Soluble Form of IL-27Rα Is a Natural IL-27 Antagonist

“…The exact role of IL-27 in CD remains to be elucidated. IL-27 can both promote and/or limit excessive Th1 response and inhibit Th17 cell differentiation, and, in murine studies of colitis, IL-27 has been associated with either promotion or attenuation of the disease, depending on the model (38)(39)(40)(41). Interestingly, human genetics studies identified polymorphisms and epigenetic modifications in p28 locus, suggesting that dysregulated p28/IL-27 production may contribute to CD pathology (27)(28)(29).…”

Paraoxonase-1 Suppresses Experimental Colitis via the Inhibition of IFN-γ Production from CD4 T Cells

“…The immune pathogenesis of TNBS-induced colitis is associated with increased levels of inflammatory cytokines, including IFN-g (46)(47)(48). Additionally, some inflammatory cytokines, such as IL-17 (32,49) and 50), play a crucial role in the induction of CD in patients and experimental colitis in mice. PON-1 inhibited the IFN-g production from both murine and human CD4 T cells (Fig.…”

“…Experimental colitis was induced by the rectal administration of a TNBS solution in mice as described previously (32). Briefly, mice were anesthetized on day 0, and a silicon catheter was inserted intrarectally (i.r.…”