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Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory responses. Whereas MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Colitis was induced in wild-type (WT) and Mal-deficient (Mal(-/-)) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total body gamma irradiation followed by transplantation of bone marrow cells. In the DSS model of colon epithelial injury, Mal(-/-) mice developed increased inflammation and severity of colitis relative to WT mice. Mal(-/-) mice demonstrated the presence of inflammatory cell infiltrates, increased crypt proliferation, and presence of neoformations. Furthermore, in the AOM/DSS model, Mal(-/-) mice had greater incidence of tumors. Mal(-/-) and WT bone marrow chimeras demonstrated that nonhematopoietic cell expression of Mal had an important protective role in the control of intestinal inflammation and inflammation-associated cancer. Mal is essential for the maintenance of intestinal homeostasis and expression of Mal in nonhematopoietic cells prevents chronic intestinal inflammation that may predispose to colon neoplasia.

Original publication

DOI

10.1152/ajpgi.00399.2013

Type

Journal article

Journal

Am J Physiol Gastrointest Liver Physiol

Publication Date

01/05/2014

Volume

306

Pages

G769 - G778

Keywords

Goll-like receptors, MyD88, bone marrow chimera, colon cancer, inflammation, Animals, Azoxymethane, Bone Marrow Transplantation, Caco-2 Cells, Colitis, Colon, Colorectal Neoplasms, Dextran Sulfate, Disease Models, Animal, Female, Homeostasis, Humans, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Interleukin-1, Severity of Illness Index, Time Factors, Transplantation Chimera