TY - JOUR
T1 - The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer
AU - Allen, Irving C.
AU - Tekippe, Erin McElvania
AU - Woodford, Rita Marie T
AU - Uronis, Joshua M.
AU - Holl, Eda K.
AU - Rogers, Arlin B.
AU - Herfarth, Hans H.
AU - Jobin, Christian
AU - Ting, Jenny P Y
PY - 2010/5/10
Y1 - 2010/5/10
N2 - 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-1β 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.
AB - 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-1β 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.
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U2 - 10.1084/jem.20100050
DO - 10.1084/jem.20100050
M3 - Article
C2 - 20385749
AN - SCOPUS:77952303410
SN - 0022-1007
VL - 207
SP - 1045
EP - 1056
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 5
ER -