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Garlanda, C. et al. Increased susceptibility to colitis-associated cancer of mice lacking TIR8, an inhibitory member of the interleukin-1 receptor family. Cancer Res. 67, 6017-6021

University of Milan, Milano, Lombardy, Italy
Cancer Research (Impact Factor: 9.28). 08/2007; 67(13):6017-21. DOI: 10.1158/0008-5472.CAN-07-0560
Source: PubMed

ABSTRACT 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 E(2), 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.

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Available from: Tania Veliz Rodriguez, Aug 28, 2015
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    • "Tir8/Sigirr-deficient colon epithelial cells revealed constitutive NF-κB and JNK activation and up-regulated expression of Cyclin D1 and Bcl-xL, which were further increased by treatment with IL-1 or LPS and returned to the control level after depletion of the commensal bacteria (Xiao et al., 2007). This spontaneous phenotype was not confirmed in other studies (Garlanda et al., 2004, 2007b), possibly a reflection of animal house-dependent variation in microbiota. "
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    • "We examined 3 specific compartments in each tissue, the epithelial compartment, the stroma and endothelial compartment. Additionally, we studied tumor tissues derived from animals lacking Tir8, an interleukin-1/Toll-like receptor family member highly expressed in the intestinal mucosa [45] in the azoxymethane and dextran sulfate sodium salt (DSS) model of CRC. In this mouse model of colonic carcinigenesis, the lack of constraints to NF-κB driven inflammation, mediated via interleukin-1 inhibition, allows investigation of the effects of enhanced inflammation. "
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    • "Excessive TLR/IL-1R–driven signaling can itself drive proinflammatory responses that fuel tumorigenesis, as shown by the MyD88-dependent development of CAC in Il10−/− mice treated with AOM (Uronis et al., 2009). Moreover, the removal of negative regulators of TLR/IL-1R family and inflammasome signaling, such as Tir8 or caspase-12, respectively, also leads to increased colitis and CAC in the DSS + AOM model (Dupaul-Chicoine et al., 2010; Garlanda et al., 2007). In addition to excessive production of inflammatory cytokines in these mice, hyperproliferative epithelial repair responses may also drive tumorigenesis. "
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