IFN‐γ induces IL‐23 producing DC‐like macrophage via suppression of endogenous IL‐10 signaling

Abstract

Recently, it has become evident that intestinal macrophages in normal intestine show anti‐inflammatory phenotypes, and play a central role in regulation of immune responses against commensal bacteria. On the other hand, we have reported that intestinal macrophages in patients with Crohn's disease (CD) revealed IL‐23‐producing pro‐inflammatory phenotypes. In this study, we have demonstrated that IFN‐γ, which contributes to the pathogenesis of CD, affected the macrophage differentiation. IFN‐γ conditioned macrophages produced larger IL‐23, and co‐expressed some DC markers on their cell surface. As a mechanism of such abnormal macrophage differentiation, we demonstrated that IFN‐γ suppressed the IL‐10 production associated with M‐CSF stimulation on macrophages. Interestingly, lamina propria conditioned media from patients with CD, which contained large amount of IFN‐γ, also suppressed the M‐CSF‐induced IL‐10 signaling, and blocking of IFN‐γ from conditioned media could rescue this suppression. Collectively, up‐regulated mucosal IFN‐γ in patients with CD induces abnormal differentiation of intestinal macrophage with IL‐23 producing DC‐like phenotypes via suppression of endogenous IL‐10 signaling. (This work was supported in part by grants‐in‐aid from the Japanese Ministry of Education, Culture, and Science and Keio Unversity Medical Fund)