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Increased Susceptibility to Colitis-Associated Cancer of Mice Lacking TIR8, an Inhibitory Member of the Interleukin-1 Receptor Family

¹ Istituto Clinico Humanitas (IRCCS), Rozzano, Italy; ² Department of Animal Pathology, Faculty of Veterinary Medicine, ³ Pathology Unit, "L. Sacco" Department of Clinical Sciences, and ⁴ Institute of General Pathology, Faculty of Medicine, University of Milan, Milan, Italy

Requests for reprints: Alberto Mantovani, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Italy. Phone: 39-2-8224-2444; Fax: 39-2-8224-5101; E-mail: alberto.mantovani{at}humanitas.it.

TIR8 (also known as SIGIRR) is a member of the interleukin-1/Toll-like receptor family with inhibitory activity on inflammatory reactions and high expression in intestinal mucosa. Here, we report that Tir8-deficient mice exhibited a dramatic intestinal inflammation in response to dextran sulfate sodium salt (DSS) administration in terms of weight loss, intestinal bleeding, and mortality and showed increased susceptibility to carcinogenesis in response to azoxymethane and DSS. Increased susceptibility to colitis-associated cancer was associated to increased permeability and local production of prostaglandin E₂, proinflammatory cytokines, and chemokines. Thus, these results are consistent with the hypothesis that TIR8, by negatively regulating intestinal inflammation, plays a nonredundant role in the control of the protumor activity of chronic inflammation in the gut. [Cancer Res 2007;67(13):6017–21]

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