title: MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18.
abstract: Signaling through the adaptor protein myeloid differentiation factor 88 (MyD88) promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88(-/-) mice to heal ulcers generated upon injury creates an altered inflammatory environment that induces early alterations in expression of genes encoding proinflammatory factors, as well as pathways regulating cell proliferation, apoptosis, and DNA repair, resulting in a dramatic increase in adenoma formation and progression to infiltrating adenocarcinomas with frequent clonal mutations in the beta-catenin gene. Others have reported that toll-like receptor (Tlr) 4-deficient mice have a similar susceptibility to colitis to Myd88-deficient mice but, unlike the latter, are resistant to CAC. We have observed that mice deficient for Tlr2 or Il1r do not show a differential susceptibility to colitis or CAC. However, upon AOM/DSS treatment Il18(-/-) and Il18r1(-/-) mice were more susceptible to colitis and polyp formation than wild-type mice, suggesting that the phenotype of Myd88(-/-) mice is, in part, a result of their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis.
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Salcedo
authors.forename: Andrea
authors.initials: A
authors.lastname: Worschech
authors.forename: Marco
authors.initials: M
authors.lastname: Cardone
authors.forename: Yava
authors.initials: Y
authors.lastname: Jones
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Gyulai
authors.forename: Ren-Ming
authors.initials: RM
authors.lastname: Dai
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Winnie
authors.initials: W
authors.lastname: Ma
authors.forename: Diana
authors.initials: D
authors.lastname: Haines
authors.forename: Colm
authors.initials: C
authors.lastname: O'hUigin
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Giorgio
authors.initials: G
authors.lastname: Trinchieri
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001397:Azoxymethane / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003111:Colonic Polyps / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D016264:Dextran Sulfate / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D051176:beta Catenin / Q000235:genetics
chemical_list: C508573:Il18r1 protein, mouse; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053573:Receptors, Interleukin-1 Type I; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051176:beta Catenin; D016264:Dextran Sulfate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D045643:DNA Repair Enzymes; D001397:Azoxymethane