The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer.
Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1beta and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3(-/-) mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3(-/-) mice than in Pycard(-/-) or Casp1(-/-) animals. No significant differences were observed in disease progression or outcome in Nlrc4(-/-) mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC.
Allen
Irving C
IC
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
TeKippe
Erin McElvania
EM
Woodford
Rita-Marie T
RM
Uronis
Joshua M
JM
Holl
Eda K
EK
Rogers
Arlin B
AB
Herfarth
Hans H
HH
Jobin
Christian
C
Ting
Jenny P-Y
JP
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics*; D003092:Colitis / Q000150:complications*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics; D005065:Euthanasia; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009369:Neoplasms / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D047368:Tumor Burden
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse
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