title: Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells.
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.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Murano
authors.affiliation: 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.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okamoto
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Ito
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakata
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Hibiya
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kano
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Yui
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Akiyama-Morio
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nemoto
authors.affiliation: 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.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: 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.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000235:genetics / Q000473:pathology; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007378:Interleukins / Q000494:pharmacology*; D000073718:Pancreatitis-Associated Proteins; D010766:Phosphorylation / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D000097043:Interleukin-22
chemical_list: D000890:Anti-Infective Agents; D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D007378:Interleukins; D000073718:Pancreatitis-Associated Proteins; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D000072056:Transcription Factor HES-1; D000097043:Interleukin-22; C000612141:REG3A protein, human; C494086:STAT3 protein, human; C078493:HES1 protein, human
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