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

作者：Allen, Irving C.; Wilson, Justin E.; Schneider, Monika; Lich, John D.; Roberts, Reid A.; Arthur, Janelle C.; Woodford, Rita-Marie T.; Davis, Beckley K.; Uronis, Joshua M.; Herfarth, Hans H.; Jobin, Christian; Rogers, Arlin B.; Ting, Jenny P. -Y.^*

来源：Immunity, 2012, 36(5): 742-754.

DOI：10.1016/j.immuni.2012.03.012

• IKK-ALPHA
• CUTTING EDGE
• MOUSE MODEL
• ACTIVATION
• INNATE
• PROTEIN
• CELLS
• CARCINOGENESIS
• RECOGNITION
• MUTATIONS

In vitro data suggest that a subgroup of NLR proteins, including NLRP12, inhibits the transcription factor NF-kappa B, although physiologic and disease-relevant evidence is largely missing. Dysregulated NF-kappa B 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-kappa B 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-kappa B 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-kappa B, inflammation, and tumorigenesis.

• 出版日期2012-5-25