Abstract
Serum level of IL-21 is increased in patients with inflammatory bowel diseases (IBD), suggesting that IL-21/IL-21 receptor (IL-21R) signaling may be involved in the pathogenesis of IBD. However, the role of IL-21/IL-21 receptor signaling plays in the pathogenesis of IBD is not very clear. In this study, using IL-21R.KO mice, we tested the role of IL-21/IL-21R signaling in the regulation of T helper cell responses during intestinal inflammation. Here we found that IL-21R.KO mice were more susceptible to DSS-induced colitis as compared with C57BL/6 mice. The spontaneous inflammatory cytokines released by macrophages in LP of colon were significantly increased, and Th2, Th17 and Treg responses were down-regulated markedly. However, Th1 responses were significantly up-regulated in IL-21R.KO mice. Meanwhile, the population of CD8+CD44+IFN-γ+ T cells was markedly elevated in LP of inflammatory intestine of IL-21RKO mice. In vivo, after disease onset, DSS-induced intestinal inflammation was ameliorated in C57BL/6 mice treated with rIL-21. Our results demonstrate that IL-21/IL-21R signaling contributes to protection against DSS-induced acute colitis through suppression of Th1 and activation of Th2, Th17 and Treg responses in mice. Therefore, therapeutic manipulation of IL-21/IL-21R activity may allow improved immunotherapy for IBD and other inflammatory diseases associated with Th cell responses.
Highlights
Of phosphoinositide 3-kinase (PI3K)/Akt and MAP kinase pathways, which are both necessary for IL-21 mediated cell proliferation[17]
We firstly examined the susceptibility of IL-21R deficient mice to DSS-induced colitis
We found that disease activity index (DAI) score significantly increased from day 6 to day 10 in IL-21RKO mice as compared to that in C57BL/6 mice after DSS-treatment (Fig. 1E, *P < 0.05; **P < 0.01)
Summary
Of phosphoinositide 3-kinase (PI3K)/Akt and MAP kinase pathways, which are both necessary for IL-21 mediated cell proliferation[17]. It is reported that IL-21 enhances T-helper cell type I signaling and IFN-γproduction in CD23. IL-21 inhibited the viability of Treg cells by inhibiting IL-2 production[25], and counteracted Treg suppression by co-stimulating CD4+ T cell proliferation and IFN-γproduction in response to TCR stimulation[26,27]. Numerous studies have demonstrated that IL-21 can significantly enhance the proliferation, survival and cytotoxic functions of CD8+ T lymphocytes[28]. Recent studies indicated that the amount of IL-21 was significantly increased in peripheral blood and intestinal tissue of patients with CD or UC23,30, suggesting that IL21/IL21R signaling is involved in the pathogenesis of IBD. We conducted following work to try to provide evidences to elucidate the roles of IL21/IL21R signaling in regulation of the mucosa immune responses during intestinal inflammation
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