Abstract
SummaryInterleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of several autoimmune and inflammatory diseases. It orchestrates innate and T cell-mediated inflammatory pathways and can promote T helper 17 (Th17) cell responses. Utilizing a T cell transfer model, we showed that IL-23-dependent colitis did not require IL-17 secretion by T cells. Furthermore, IL-23-independent intestinal inflammation could develop if immunosuppressive pathways were reduced. The frequency of naive T cell-derived Foxp3+ cells in the colon increased in the absence of IL-23, indicating a role for IL-23 in controlling regulatory T cell induction. Foxp3-deficient T cells induced colitis when transferred into recipients lacking IL-23p19, showing that IL-23 was not essential for intestinal inflammation in the absence of Foxp3. Taken together, our data indicate that overriding immunosuppressive pathways is an important function of IL-23 in the intestine and could influence not only Th17 cell activity but also other types of immune responses.
Highlights
Identifying tissue-specific factors that control the immune response is important for designing targeted therapies
Naive CD4+ CD45RBhi T cells transferred into immunodeficient hosts react to the intestinal flora to induce IL-23-dependent colonic inflammation (Hue et al, 2006; Powrie et al, 1993)
Because IL-23 promotes IL-17 production by CD4+ T cells, we reasoned that colitis might be dependent on T cell-derived IL-17
Summary
Identifying tissue-specific factors that control the immune response is important for designing targeted therapies. Recent studies have highlighted the role of IL-23 as an important mediator of tissue inflammatory responses. Interleukin-23 (IL-23) is a member of the IL-12 family of heterodimeric cytokines. It is composed of IL-12p40, which is common to IL-12, and the IL-23-specific p19 subunit (Kastelein et al, 2007; Oppmann et al, 2000). IL-23 has been shown to be important in a number of inflammatory diseases including experimental autoimmune encephalitis (EAE), collagen-induced arthritis (CIA), colitis, and dermal inflammation (Cua et al, 2003; Murphy et al, 2003; Uhlig et al, 2006b; Zheng et al, 2007). In various models of intestinal inflammation, IL-23 has been shown to be preferentially expressed in the intestine rather than in the spleen, suggesting a tissue-specific function (Hue et al, 2006; Uhlig et al, 2006b)
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