title: A Novel Role of Spred2 in the Colonic Epithelial Cell Homeostasis and Inflammation.
abstract: Rapid and adequate mucosal healing is important for a remission of ulcerative colitis (UC) patients. Here, we examined whether Spred2, a member of the Sprouty-related EVH1-domain-containing proteins that inhibit the Ras/Raf/ERK pathway, plays a role in colonic mucosal homeostasis and inflammation by using Spred2 knockout (KO) mice. We first detected increased epithelial cell proliferation and cadherin 1 expression in the colon of naïve Spred2 KO mice compared to wild-type mice. Interestingly, Spred2 KO mice were resistant to dextran sulfate sodium (DSS)-induced acute colitis as indicated by lower levels of body weight loss and disease activity index. Histologically, epithelial cell injury and inflammation were milder in the colonic mucosa of Spred2 KO mice on day 3 and almost undetectable by day 8. Experiments with bone chimeric mice indicated that Spred2-deficiency in non-hematopoietic cells was responsible for the reduced sensitivity to DSS. Finally, Spred2 KO mice developed significantly fewer tumors in response to azoxymethane plus DSS. Taken together, our results demonstrate, for the first time, that Spred2 plays an important role in the regulation of colonic epithelial cell proliferation and inflammation by potentially down-regulating the activation of ERK. Thus, Spred2 may be a new therapeutic target for the treatment of UC.
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.|Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Sakuma
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Teizo
authors.initials: T
authors.lastname: Yoshimura
authors.affiliation: Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ohkura
authors.affiliation: Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Fujisawa
authors.affiliation: Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Fushimi
authors.affiliation: Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.|Department of Immunology, Nara Medical University, Nara, 634-8521, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Itakura
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Hiraoka
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okada
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsukawa
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006706:Homeostasis; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D015820:Cadherins; D012097:Repressor Proteins; C433764:Spred2 protein, mouse; D016264:Dextran Sulfate; D001973:Bromodeoxyuridine