title: Enhanced Mucosal Defense and Reduced Tumor Burden in Mice with the Compromised Negative Regulator IRAK-M.
abstract: Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m-/-mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m-/-animals are protected against colitis and colitis associated tumorigenesis. Mechanistically, our data revealed that the gastrointestinal immune system of Irak-m-/-mice is highly efficient at eliminating microbial translocation following epithelial barrier damage. This attenuation of pathogenesis is associated with expanded areas of gastrointestinal associated lymphoid tissue (GALT), increased neutrophil migration, and enhanced T-cell recruitment. Further evaluation of Irak-m-/-mice revealed a splice variant that robustly activates NF-κB signaling. Together, these data identify IRAK-M as a potential target for future therapeutic intervention.
authors.affiliation: Department of Biomedical Sciences and Pathobiology, VA-MD College of Veterinary Medicine, Blacksburg, Virginia 24061, United States.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Rothschild
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic and State University, Blacksburg, Virginia 24061, United States.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic and State University, Blacksburg, Virginia 24061, United States.
authors.forename: Na
authors.initials: N
authors.lastname: Diao
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic and State University, Blacksburg, Virginia 24061, United States.
authors.forename: Christina K
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic and State University, Blacksburg, Virginia 24061, United States.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Biomedical Sciences and Pathobiology, VA-MD College of Veterinary Medicine, Blacksburg, Virginia 24061, United States.
authors.forename: Clayton C
authors.initials: CC
authors.lastname: Caswell
authors.affiliation: Department of Biochemistry, Virginia Polytechnic and State University, Blacksburg, Virginia 24061, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Slade
authors.affiliation: Department of Biochemistry, Virginia Polytechnic and State University, Blacksburg, Virginia 24061, United States.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Helm
authors.affiliation: Department of Biomedical Sciences and Pathobiology, VA-MD College of Veterinary Medicine, Blacksburg, Virginia 24061, United States.
authors.forename: Tanya
authors.initials: T
authors.lastname: LeRoith
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic and State University, Blacksburg, Virginia 24061, United States. Electronic address: lwli@vt.edu.
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biomedical Sciences and Pathobiology, VA-MD College of Veterinary Medicine, Blacksburg, Virginia 24061, United States. Electronic address: icallen@vt.edu.
authors.forename: Irving C
authors.initials: IC
authors.lastname: Allen
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D018928:Immunity, Mucosal; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse
keywords: Colitis; Colitis associated cancer; GALT; IRAK-M; Inflammatory bowel disease