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 prote...

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Veröffentlicht in:The Journal of experimental medicine 2010-05, Vol.207 (5), p.1045-1056
Hauptverfasser: Allen, Irving C, TeKippe, Erin McElvania, Woodford, Rita-Marie T, Uronis, Joshua M, Holl, Eda K, Rogers, Arlin B, Herfarth, Hans H, Jobin, Christian, Ting, Jenny P-Y
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container_issue 5
container_start_page 1045
container_title The Journal of experimental medicine
container_volume 207
creator Allen, Irving C
TeKippe, Erin McElvania
Woodford, Rita-Marie T
Uronis, Joshua M
Holl, Eda K
Rogers, Arlin B
Herfarth, Hans H
Jobin, Christian
Ting, Jenny P-Y
description 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.
doi_str_mv 10.1084/jem.20100050
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subjects Animals
Apoptosis Regulatory Proteins
CARD Signaling Adaptor Proteins
Carrier Proteins - genetics
Colitis - complications
Colon - metabolism
Colon - pathology
Cytoskeletal Proteins - deficiency
Cytoskeletal Proteins - genetics
Euthanasia
Gene Expression Regulation, Neoplastic
Humans
Inflammatory Bowel Diseases - complications
Interleukin-18 - metabolism
Interleukin-1beta - metabolism
Mice
Mice, Knockout
Neoplasms - etiology
Neoplasms - pathology
Neoplasms - prevention & control
NLR Family, Pyrin Domain-Containing 3 Protein
Tumor Burden
title The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer
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