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.

Download full-text


Available from: Tania Veliz Rodriguez, Oct 05, 2015
26 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The epithelial layers that line the human gut and airways have evolved into tightly regulated mechanical and functional tissue barriers, the mucosae, which have to cope with unrelenting exposure to food-and airborne contaminants. In these barriers, immune cells play a major defensive role. This review describes the most important cellular and molecular mechanisms of mucosal leukocytes during homeostasis and physiological inflammation with a major focus on innate immunity (i.e. the immediate response against potential invaders). In homeostasis, a well-defined mucus layer and the epithelial layer hinder microbes from entering the underlying tissue. In addition, mucosal macrophages are patrolling scavengers with high phagocytic capacity, but their ability to mount an inflammatory response is down-regulated. Innate lymphoid cells also have an important role in maintaining a healthy mucosa. However, if bacteria overcome the barrier they cause an inflammatory reaction aimed at eliminating the threat and re-establishing tissue homeostasis. During the inflammatory response, tissue-resident immune cells become activated and promote the recruitment of monocytes and other leukocytes from the blood to the site of inflammation. The reaction evolves the contribution of mononuclear phagocytes, mast cells, neutrophils and ILCs until the infection is eliminated, tissue damage repaired and homeostasis re-established.
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Frontiers in Immunology 10/2012; 3:322. DOI:10.3389/fimmu.2012.00322
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer can be efficiently treated when found at early stages, thus the search for novel markers is of paramount importance. Since inflammation is associated with cancer progression and angiogenesis, we investigated expression of cytokines like IL-6 and other mediators that play a key role in the innate immune system, in particular toll like receptor 4 (TLR4), in the microenvironment of lesions from different stages of colon disease progression, from ulcerative colitis to adenoma and adenocarcinoma to find useful markers. The presence of inflammatory cells and expression of key cytokines involved in the inflammation process were quantified by immunohistochemistry in specific tissue compartments (epithelial, stromal, endothelial) by immunohistochemistry. A murine azoxymethane/dextran sulfate model in which Tir8, a negative regulator of the inflammatory response, was ablated was used to confirm the clinical observations. 116 Archival tissue samples from patients with different stages of colorectal disease: 13 cases of ulcerative colitis (UC), 34 tubular or tubulo-villous adenomas (AD), and 53 infiltrating adenocarcinomas. 16 specimens of healthy mucosa surgically removed with the cancerous tissue were used as a control. The differences between healthy tissues and the diverse lesions was characterized by a marked inflammatory-angiogenic reaction, with significantly (P < 0.05) higher numbers of CD68, CD15, and CD31 expressing cells in all diseased tissues that correlated with increasing grade of malignancy. We noted down-regulation of a potential modulator molecule, Hepatocyte Growth Factor, in all diseased tissues (P < 0.05). TLR-4 and IL6 expression in the tumor microenvironment were associated with adenocarcinoma in human samples and in the murine model. We found that adenocarcinoma patients (pT1-4) with higher TLR-4 expression in stromal compartment had a significantly increased risk in disease progression. In those patients with a diagnosis of pT3 (33 cases) colon cancer, those with very high levels of TLR-4 in the tumor stroma relapsed significantly earlier than those with lower expression levels. These data suggest that high TLR-4 expression in the tumor microenvironment represents a possible marker of disease progression in colon cancer.
    Journal of Translational Medicine 11/2010; 8(1):112. DOI:10.1186/1479-5876-8-112 · 3.93 Impact Factor
Show more