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

University of Milan, Milano, Lombardy, Italy
Cancer Research (Impact Factor: 9.33). 08/2007; 67(13):6017-21. DOI: 10.1158/0008-5472.CAN-07-0560
Source: PubMed


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
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    • "Deficiency of SIGIRR was associated with both dramatic intestinal inflammation [29] and an increased susceptibility to acute lung infection [30]. During inflammation, however, SIGIRR expression is reduced in intestinal epithelial cells in order to ensure proper TLR signaling [31]. "
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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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    ABSTRACT: Interleukin-1R like receptors (ILRs) and Toll Like Receptors (TLRs) are key receptors of innate immunity, inflammation, and orientation of the adaptive response. They belong to a superfamily characterized by the presence of a conserved intracellular domain, the Toll/IL-1R (TIR) domain, which is involved in the activation of a signaling cascade leading to activation of transcription factors associated to inflammation. The activation of inflammatory responses and immunity by ILRs or TLRs signaling is potentially detrimental for the host in acute and chronic conditions and is tightly regulated at different levels by receptor antagonists, decoy receptors or signaling molecules, and miRNAs. Recent evidence suggests that the ILRs family member TIR8 (also known as SIGIRR) is a regulatory protein acting intracellularly to inhibit ILRs and TLRs signaling. In particular, current evidence suggests that TIR8/SIGIRR dampens TLRs-mediated activation and inhibits signaling receptor complexes of IL-1 family members associated with Th1 (IL-18), Th2 (IL-33), and Th17 (IL-1) differentiation. Studies with Tir8/Sigirr-deficient mice showed that the ability to dampen signaling from ILRs and TLRs family members makes TIR8/SIGIRR a key regulator of inflammation. Here, we summarize our current understanding of the structure and function of TIR8/SIGIRR, focusing on its role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation.
    Preview · Article · Oct 2012 · Frontiers in Immunology
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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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