title: Absence of bacterially induced RELMbeta reduces injury in the dextran sodium sulfate model of colitis.
abstract: Although inflammatory bowel disease (IBD) is the result of a dysregulated immune response to commensal gut bacteria in genetically predisposed individuals, the mechanism(s) by which bacteria lead to the development of IBD are unknown. Interestingly, deletion of intestinal goblet cells protects against intestinal injury, suggesting that this epithelial cell lineage may produce molecules that exacerbate IBD. We previously reported that resistin-like molecule beta (RELMbeta; also known as FIZZ2) is an intestinal goblet cell-specific protein that is induced upon bacterial colonization whereupon it is expressed in the ileum and colon, regions of the gut most often involved in IBD. Herein, we show that disruption of this gene reduces the severity of colitis in the dextran sodium sulfate (DSS) model of murine colonic injury. Although RELMbeta does not alter colonic epithelial proliferation or barrier function, we show that recombinant protein activates macrophages to produce TNF-alpha both in vitro and in vivo. RELMbeta expression is also strongly induced in the terminal ileum of the SAMP1/Fc model of IBD. These results suggest a model whereby the loss of epithelial barrier function by DSS results in the activation of the innate mucosal response by RELMbeta located in the lumen, supporting the hypothesis that this protein is a link among goblet cells, commensal bacteria, and the pathogenesis of IBD.
authors.affiliation: Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Laila D
authors.initials: LD
authors.lastname: McVay
authors.forename: Sue A
authors.initials: SA
authors.lastname: Keilbaugh
authors.forename: Tracie M H
authors.initials: TM
authors.lastname: Wong
authors.forename: Sonja
authors.initials: S
authors.lastname: Kierstein
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Shin
authors.forename: Michael
authors.initials: M
authors.lastname: Lehrke
authors.forename: Martina I
authors.initials: MI
authors.lastname: Lefterova
authors.forename: D Edward
authors.initials: DE
authors.lastname: Shifflett
authors.forename: Sean L
authors.initials: SL
authors.lastname: Barnes
authors.forename: Fabio
authors.initials: F
authors.lastname: Cominelli
authors.forename: Steven M
authors.initials: SM
authors.lastname: Cohn
authors.forename: Gail
authors.initials: G
authors.lastname: Hecht
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.forename: Angela
authors.initials: A
authors.lastname: Haczku
authors.forename: Gary D
authors.initials: GD
authors.lastname: Wu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D016264:Dextran Sulfate / Q000494:pharmacology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006729:Hormones, Ectopic / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D007958:Leukocyte Count; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout
chemical_list: D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; C486522:Retnlb protein, mouse; D016264:Dextran Sulfate