title: Bcl-3 deficiency protects against dextran-sodium sulphate-induced colitis in the mouse.
abstract: Bcl-3 is a member of the IκB family of proteins and is an essential negative regulator of Toll-like receptor-induced responses. Recently, a single nucleotide polymorphism associated with reduced Bcl-3 gene expression has been identified as a potential risk factor for Crohn's disease. Here we report that in contrast to the predictions of single nucleotide polymorphism (SNP) analysis, patients with Crohn's disease and ulcerative colitis demonstrate elevated Bcl-3 mRNA expression relative to healthy individuals. To explore further the potential role of Bcl-3 in inflammatory bowel disease (IBD), we used the dextran-sodium sulphate (DSS)-induced model of colitis in Bcl-3(-/-) mice. We found that Bcl-3(-/-) mice were less sensitive to DSS-induced colitis compared to wild-type controls and demonstrated no significant weight loss following treatment. Histological analysis revealed similar levels of oedema and leucocyte infiltration between DSS-treated wild-type and Bcl-3(-/-) mice, but showed that Bcl-3(-/-) mice retained colonic tissue architecture which was absent in wild-type mice following DSS treatment. Analysis of the expression of the proinflammatory cytokines interleukin (IL)-1β, tumour necrosis factor (TNF)-α and IL-6 revealed no significant differences between DSS-treated Bcl-3(-/-) and wild-type mice. Analysis of intestinal epithelial cell proliferation revealed enhanced proliferation in Bcl-3(-/-) mice, which correlated with preserved tissue architecture. Our results reveal that Bcl-3 has an important role in regulating intestinal epithelial cell proliferation and sensitivity to DSS-induced colitis which is distinct from its role as a negative regulator of inflammation.
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: O'Carroll
authors.forename: G
authors.initials: G
authors.lastname: Moloney
authors.forename: G
authors.initials: G
authors.lastname: Hurley
authors.forename: S
authors.initials: S
authors.lastname: Melgar
authors.forename: E
authors.initials: E
authors.lastname: Brint
authors.forename: K
authors.initials: K
authors.lastname: Nally
authors.forename: R J
authors.initials: RJ
authors.lastname: Nibbs
authors.forename: F
authors.initials: F
authors.lastname: Shanahan
authors.forename: R J
authors.initials: RJ
authors.lastname: Carmody
mesh_terms: D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D048708:Cell Growth Processes / Q000235:genetics; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000276:immunology* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000008:administration & dosage; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015431:Weight Loss / Q000235:genetics
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D016264:Dextran Sulfate
keywords: animal models/studies - mice/rats; epithelial cells; gut immunology/disease; inflammatory bowel disease; proliferation