Interferon-γ inhibits sirtuin 6 gene expression in intestinal epithelial cells through a -dependent mechanism.

Sirtuin 6 (Sirt6) is predominantly expressed in epithelial cells in intestinal crypts. It plays an important role in protecting intestinal epithelial cells against inflammatory injury. Previously, we found that colitis is associated with the downregulation of Sirt6 protein in the intestines. Here, we report that murine interferon-γ (Ifnγ) inhibits Sirt6 protein but not mRNA expression in young adult mouse colonocytes (YAMC, a mouse colonic epithelial cell line) in a dose- and time-dependent manner. Using microRNA array analysis, we showed that Ifnγ induces expression of in YAMC cells. With in silico analysis, we found that the 3'-untranslated region (UTR) contains a putative binding site for . Luciferase assay showed that Ifnγ inhibited 3'-UTR activity and this effect was mimicked by via directly targeting the seed site in the 3'-UTR of mRNA. Furthermore, Western blot demonstrated that downregulated Sirt6 protein expression in YAMC cells. Blocking with a specific inhibitor attenuated the inhibitory effect of Ifnγ on Sirt6 protein expression in the cells. Collectively, our data suggest that Ifnγ inhibits Sirt6 protein expression in intestinal epithelial cells via a -mediated mechanism. may be a novel therapeutic target for rescuing Sirt6 protein levels in intestinal epithelial cells, thereby protecting against intestinal mucosal injury caused by inflammation.