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Biochem Biophys Res Commun. 2014 Jan 17;443(3):840-6. doi: 10.1016/j.bbrc.2013.12.061. Epub 2013 Dec 14.

Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells.

Author information

1
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
2
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; Department of Advanced GI Therapeutics, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: rokamoto.gast@tmd.ac.jp.
3
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; Department of Advanced GI Therapeutics, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract

Notch signaling plays an essential role in the proliferation and differentiation of intestinal epithelial cells (IECs). We have previously shown that Notch signaling is up-regulated in the inflamed mucosa of ulcerative colitis (UC) and thereby plays an indispensable role in tissue regeneration. Here we show that in addition to Notch signaling, STAT3 signaling is highly activated in the inflamed mucosa of UC. Forced expression of the Notch target gene Hes1 dramatically enhanced the IL-22-mediated STAT3-dependent transcription in human IECs. This enhancement of STAT3-dependent transcription was achieved by the extended phosphorylation of STAT3 by Hes1. Microarray analysis revealed that Hes1-mediated enhancement of IL-22-STAT3 signaling significantly increased the induction of genes encoding antimicrobial peptides, such as REG1A, REG3A and REG3G, in human IECs. Conversely, the reduction of Hes1 protein levels with a γ-secretase inhibitor significantly down-regulated the induction of those genes in IECs, resulting in a markedly poor response to IL-22. Our present findings identify a new role for the molecular function of Hes1 in which the protein can interact with cytokine signals and regulate the immune response of IECs.

KEYWORDS:

DOX; GSI; HES1; IECs; IL-22; Notch signaling; STAT3; UC; Ulcerative colitis; doxycycline; intestinal epithelial cells; p-STAT3; phosphorylated STAT3; ulcerative colitis; γ-secretase inhibitor

PMID:
24342613
DOI:
10.1016/j.bbrc.2013.12.061
[Indexed for MEDLINE]

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