IL-18 Production Downstream of the Nlrp3 Inflammasome Confers Protection against Colorectal Tumor Formation

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(8):4912-20. DOI: 10.4049/jimmunol.1002046
Source: PubMed


Colorectal cancer is a leading cause of cancer-related deaths worldwide. Chronic inflammation is recognized as a predisposing factor for the development of colon cancer, but the molecular mechanisms linking inflammation and tumorigenesis have remained elusive. Recent studies revealed a crucial role for the NOD-like receptor protein Nlrp3 in regulating inflammation through the assembly of proinflammatory protein complexes termed inflammasomes. However, its role in colorectal tumor formation remains unclear. In this study, we showed that mice deficient for Nlrp3 or the inflammasome effector caspase-1 were highly susceptible to azoxymethane/dextran sodium sulfate-induced inflammation and suffered from dramatically increased tumor burdens in the colon. This was a consequence of markedly reduced IL-18 levels in mice lacking components of the Nlrp3 inflammasome, which led to impaired production and activation of the tumor suppressors IFN-γ and STAT1, respectively. Thus, IL-18 production downstream of the Nlrp3 inflammasome is critically involved in protection against colorectal tumorigenesis.

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    • "Another study showed prolonged colitis and epithelial destruction in Nlrp6−/− mice after DSS treatment was related to alterations in commensal microbiota, and was phenocopied when mice were deficient in any of the NLRP6 inflammasome components ASC (a common adapter to many inflammasomes), and caspase-1 (17). The IL-18 cytokine, cleaved into its biologically active form by activated caspase-1, has emerged as a key cytokine downstream of inflammasome activation that enables epithelial repair after damage, but also prevents cancer progression through its induction of the tumor suppressors STAT1 and IFN-γ (18). When treated with AOM/DSS, the resulting increased epithelial proliferation and exacerbated inflammation in Nlrp6−/− mice led to accelerated outgrowth of colonic cancer (16). "
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    Frontiers in Immunology 04/2014; 5:185. DOI:10.3389/fimmu.2014.00185
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    • "Inflammasome forming NLRs significantly regulate the tumor microenvironment by modulating cytokine production. For example, many of the inflammasome forming NLRs have been shown to significantly attenuate inflammation and tumorigenesis in mouse models of colitis-associated colorectal cancer (CAC) by regulating IL-18 production (18, 19, 21, 22, 38–40). In addition to being a potent pro-inflammatory cytokine, IL-18 is also secreted by epithelial cells to stimulate regeneration and repair and improve barrier function in the colon, thus loss of this cytokine in NLR inflammasome deficient mice enhances tumorigenesis (41). "
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    Frontiers in Immunology 04/2014; 5:169. DOI:10.3389/fimmu.2014.00169
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    • "Human monocyte-derived dendritic cells (DCs), when matured in the presence of butyrate, have increased expression of IL-10 and decreased production of IL-6 (Millard et al., 2002; Wang et al., 2008). IL- 18 plays an essential role in suppression of colonic inflammation and inflammation-associated cancers (Chen et al., 2011; Dupaul-Chicoine et al., 2010; Elinav et al., 2011; Salcedo et al., 2010; Zaki et al., 2010). Moreover, an IL-18 gene promoter polymorphism leading to decreased expression is found at higher frequency in patients with ulcerative colitis (Takagawa et al., 2005). "
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