Journal
IMMUNITY
Volume 36, Issue 5, Pages 742-754Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2012.03.012
Keywords
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Categories
Funding
- CCFA
- UNC-CH UCRF
- American Cancer Society
- [R21CA131645]
- [CA156330]
- [AI077437]
- [AI067798]
- [AR007416]
- [K01DK092355]
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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.
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