title: Epimorphin(-/-) mice are protected, in part, from acute colitis via decreased interleukin 6 signaling.
abstract: Epimorphin (Epim), a member of the syntaxin family of membrane-bound, intracellular vesicle-docking proteins, is expressed in intestinal myofibroblasts and macrophages. We demonstrated previously that Epimorphin(-/-)(Epim(-/-)) mice are protected, in part, from dextran sodium sulfate (DSS)-induced colitis. Although interleukin (IL)-6/p-Stat3 signaling has been implicated in the pathogenesis of colitis, the myofibroblast contribution to IL-6 signaling in colitis remains unexplored. Our aim was to investigate the IL-6 pathway in Epim(-/-) mice in the DSS colitis model. Whole colonic tissue, epithelium, and stroma of WT and congenic Epim(-/-) mice treated with 5% DSS for 7 days were analyzed for IL-6 and a downstream effector, p-Stat3, by immunostaining and immunoblot. Colonic myofibroblast and peritoneal macrophage IL-6 secretion were evaluated by enzyme-linked immunosorbent assay. IL-6 and p-Stat3 expression were decreased in Epim(-/-) vs WT colon. A relative increase in stromal vs epithelial p-Stat3 expression was observed in WT mice but not in Epim(-/-) mice. Epim deletion abrogates IL-6 secretion from colonic myofibroblasts treated with IL-1β and decreases IL-6 secretion from peritoneal macrophages in a subset of DSS-treated mice. Epim deletion inhibits IL-6 secretion most profoundly from colonic myofibroblasts. Distribution of Stat3 activation is altered in DSS-treated Epim(-/-) mice. Our findings support the notion that myofibroblasts modulate IL-6/p-Stat3 signaling in DSS-treated Epim(-/-) mice.
authors.affiliation: Divisions of Gastroenterology and Hepatology, Keck School of Medicine of USC, Los Angeles, CA. Electronic address: ashaker@usc.edu.
authors.forename: Anisa
authors.initials: A
authors.lastname: Shaker
authors.affiliation: Divisions of Gastroenterology and Hepatology, Keck School of Medicine of USC, Los Angeles, CA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gargus
authors.affiliation: Divisions of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Mo.
authors.forename: Julie
authors.initials: J
authors.lastname: Fink
authors.affiliation: Divisions of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Mo.
authors.forename: Jana
authors.initials: J
authors.lastname: Binkley
authors.affiliation: Divisions of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Mo.
authors.forename: Isra
authors.initials: I
authors.lastname: Darwech
authors.affiliation: Divisions of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Mo.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Swietlicki
authors.affiliation: Divisions of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Mo; Department of Medicine, St. Louis Health Care System, St. Louis, Mo.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Levin
authors.affiliation: Divisions of Gastroenterology and Hepatology, Washington University School of Medicine, St. Louis, Mo.
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Rubin
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced*; D016264:Dextran Sulfate / Q000633:toxicity; D005786:Gene Expression Regulation / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction
chemical_list: C504582:Epim protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D016264:Dextran Sulfate
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