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PMID: 20624890 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural

MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18.

The Journal of experimental medicine ·Vol. 207 ·No. 8 ·2010-08-02 ·Pages 1625-36

Salcedo R, Worschech A, Cardone M, Jones Y, Gyulai Z, Dai RM, Wang E, Ma W, Haines D, O'hUigin C, Marincola FM, Trinchieri G

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.

MeSH Terms
Adenocarcinoma/chemically induced,genetics,metabolism,pathology Animals Apoptosis/drug effects,genetics Azoxymethane/pharmacology Cell Proliferation/drug effects Colon/drug effects,metabolism,pathology Colonic Neoplasms/chemically induced,genetics,metabolism,pathology Colonic Polyps/pathology Cyclooxygenase 2/genetics DNA Repair Enzymes/genetics Dextran Sulfate/pharmacology Epithelial Cells/drug effects,metabolism,pathology Gene Expression/drug effects,genetics Gene Expression Profiling Genetic Predisposition to Disease/genetics Inflammatory Bowel Diseases/chemically induced,genetics,metabolism,pathology Interleukin-18/genetics,metabolism Interleukin-18 Receptor alpha Subunit/genetics Intestinal Mucosa/drug effects,metabolism,pathology Mice Mice, Inbred C57BL Mice, Knockout Mutation/genetics Myeloid Differentiation Factor 88/metabolism Phosphorylation/drug effects Receptors, Interleukin-1 Type I/genetics STAT3 Transcription Factor/genetics Signal Transduction/physiology Specific Pathogen-Free Organisms beta Catenin/genetics
Chemicals
Il18r1 protein, mouse Interleukin-18 Interleukin-18 Receptor alpha Subunit Myd88 protein, mouse Myeloid Differentiation Factor 88 Receptors, Interleukin-1 Type I STAT3 Transcription Factor Stat3 protein, mouse beta Catenin Dextran Sulfate Ptgs2 protein, mouse Cyclooxygenase 2 DNA Repair Enzymes Azoxymethane
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Salcedo Rosalba
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA.
Worschech Andrea
Cardone Marco
Jones Yava
Gyulai Zsofia
Dai Ren-Ming
Wang Ena
Ma Winnie
Haines Diana
O'hUigin Colm
Marincola Francesco M
Trinchieri Giorgio
References (41)
41 references, click to expand
  1. Lack of interferon-gamma production despite the presence of interleukin-18 during cutaneous wound healing.
    Mol Med. 2000 Dec;6(12):1016-27 PMID: 11474118
  2. MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis.
    J Gastroenterol. 2005 Jan;40(1):16-23 PMID: 15692785
  3. Epithelial NEMO links innate immunity to chronic intestinal inflammation.
    Nature. 2007 Mar 29;446(7135):557-61 PMID: 17361131
  4. Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice.
    Scand J Gastroenterol. 2003 Aug;38(8):837-44 PMID: 12940437
  5. Interferons, immunity and cancer immunoediting.
    Nat Rev Immunol. 2006 Nov;6(11):836-48 PMID: 17063185
  6. Deletion of TLR5 results in spontaneous colitis in mice.
    J Clin Invest. 2007 Dec;117(12):3909-21 PMID: 18008007
  7. Interleukin-18 and the pathogenesis of inflammatory diseases.
    Semin Nephrol. 2007 Jan;27(1):98-114 PMID: 17336692
  8. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice.
    J Clin Invest. 2008 May;118(5):1727-38 PMID: 18431520
  9. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis.
    Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):652-6 PMID: 18178624
  10. Cluster analysis and display of genome-wide expression patterns.
    Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8 PMID: 9843981
  11. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.
    Cell. 2004 Jul 23;118(2):229-41 PMID: 15260992
  12. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface.
    Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20858-63 PMID: 19075245
  13. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility.
    PLoS One. 2009 Jun 24;4(6):e6026 PMID: 19551144
  14. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling.
    Nat Med. 2005 Aug;11(8):845-52 PMID: 16041381
  15. Stabilization of beta-catenin by genetic defects in melanoma cell lines.
    Science. 1997 Mar 21;275(5307):1790-2 PMID: 9065403
  16. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.
    Cell. 2004 Aug 6;118(3):285-96 PMID: 15294155
  17. Systematic variation in gene expression patterns in human cancer cell lines.
    Nat Genet. 2000 Mar;24(3):227-35 PMID: 10700174
  18. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis.
    Immunity. 2007 Apr;26(4):461-75 PMID: 17398123
  19. Novel genetic markers in inflammatory bowel disease.
    World J Gastroenterol. 2007 Nov 14;13(42):5560-70 PMID: 17948929
  20. Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases.
    Immunity. 2010 Mar 26;32(3):367-78 PMID: 20226691
  21. STATs in cancer inflammation and immunity: a leading role for STAT3.
    Nat Rev Cancer. 2009 Nov;9(11):798-809 PMID: 19851315
  22. Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury.
    J Clin Invest. 2007 Jan;117(1):258-69 PMID: 17200722
  23. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer.
    Cancer Cell. 2009 Feb 3;15(2):103-13 PMID: 19185845
  24. Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells.
    Cancer Cell. 2009 Sep 8;16(3):208-19 PMID: 19732721
  25. beta-Catenin mutation is selected during malignant transformation in colon carcinogenesis.
    Carcinogenesis. 2003 Jan;24(1):91-7 PMID: 12538353
  26. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury.
    Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):99-104 PMID: 15615857
  27. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88.
    Science. 2007 Jul 6;317(5834):124-7 PMID: 17615359
  28. Prospective molecular profiling of melanoma metastases suggests classifiers of immune responsiveness.
    Cancer Res. 2002 Jul 1;62(13):3581-6 PMID: 12097256
  29. IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice.
    J Exp Med. 2006 Jun 12;203(6):1391-7 PMID: 16717119
  30. DNA damage response as an anti-cancer barrier: damage threshold and the concept of 'conditional haploinsufficiency'.
    Cell Cycle. 2007 Oct 1;6(19):2344-7 PMID: 17700066
  31. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis.
    J Clin Invest. 2005 Mar;115(3):695-702 PMID: 15765149
  32. Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP.
    Am J Hum Genet. 2008 May;82(5):1202-10 PMID: 18439550
  33. Commentary: the role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe?
    Eur J Immunol. 2004 Sep;34(9):2347-55 PMID: 15307167
  34. The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis.
    Immunity. 2010 Mar 26;32(3):379-91 PMID: 20303296
  35. CpG motifs of bacterial DNA essentially contribute to the perpetuation of chronic intestinal inflammation.
    Gastroenterology. 2005 Sep;129(3):913-27 PMID: 16143131
  36. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications.
    Clin Genet. 2009 Jul;76(1):1-18 PMID: 19659756
  37. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.
    Science. 2007 Jul 6;317(5834):121-4 PMID: 17615358
  38. Common cancer biomarkers.
    Cancer Res. 2006 Mar 15;66(6):2953-61 PMID: 16540643
  39. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors.
    Gastroenterology. 2007 Dec;133(6):1869-81 PMID: 18054559
  40. Signaling molecules: the pathogenic role of the IL-6/STAT-3 trans signaling pathway in intestinal inflammation and in colonic cancer.
    Curr Drug Targets. 2008 May;9(5):369-74 PMID: 18473764
  41. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis.
    Am J Physiol Gastrointest Liver Physiol. 2005 May;288(5):G1055-65 PMID: 15826931
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20100199
Published
2010-08-02
Epub
2010-00-12
Pages
1625-36
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2916129
Subset
IM
Grants
CCR NIH HHS · HHSN261200800001C · United States
NCI NIH HHS · HHSN261200800001E · United States
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1084/jem.20100199 PMC Full Text View journal details
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