NLRP12 Suppresses Colon Inflammation and Tumorigenesis through the Negative Regulation of Noncanonical NF-κB Signaling

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Immunity (Impact Factor: 21.56). 04/2012; 36(5):742-54. DOI: 10.1016/j.immuni.2012.03.012
Source: PubMed


In vitro data suggest that a subgroup of NLR proteins, including NLRP12, inhibits the transcription factor NF-κB, although physiologic and disease-relevant evidence is largely missing. Dysregulated NF-κB activity is associated with colonic inflammation and cancer, and we found Nlrp12(-/-) mice were highly susceptible to colitis and colitis-associated colon cancer. Polyps isolated from Nlrp12(-/-) mice showed elevated noncanonical NF-κB activation and increased expression of target genes that were associated with cancer, including Cxcl13 and Cxcl12. NLRP12 negatively regulated ERK and AKT signaling pathways in affected tumor tissues. Both hematopoietic- and nonhematopoietic-derived NLRP12 contributed to inflammation, but the latter dominantly contributed to tumorigenesis. The noncanonical NF-κB pathway was regulated upon degradation of TRAF3 and activation of NIK. NLRP12 interacted with both NIK and TRAF3, and Nlrp12(-/-) cells have constitutively elevated NIK, p100 processing to p52 and reduced TRAF3. Thus, NLRP12 is a checkpoint of noncanonical NF-κB, inflammation, and tumorigenesis.

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    • "Further, NLRP12 was reported to contribute to IL-1 and IL-18 production in response to Yersinia pestis (Vladimer et al., 2012), and IL-1 production during malaria-associated sepsis (Ataide et al., 2014). Several reports implicate NLRP12 in the suppression of NF-B and ERK signalling pathways in murine macrophages, dendritic cells (DCs), or human THP-1 monocytic cells (Allen et al., 2012; Lich et al., 2007; Williams et al., 2005; Zaki et al., 2013, 2011). Other reports suggest that NLRP12 drives cell migration in murine neutrophils and DC "
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