The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer

Irving C. Allen, Erin McElvania Tekippe, Rita Marie T Woodford, Joshua M. Uronis, Eda K. Holl, Arlin B. Rogers, Hans H. Herfarth, Christian Jobin, Jenny P Y Ting

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1045-1056
Number of pages12
JournalJournal of Experimental Medicine
Volume207
Issue number5
DOIs
StatePublished - May 10 2010

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Inflammasomes
Colitis
Carcinogenesis
Neoplasms
Dextran Sulfate
Azoxymethane
Caspase 1
Interleukin-18
Wild Animals
Stromal Cells
Polyps
Tumor Burden
Interleukin-1
Inflammatory Bowel Diseases
Leucine
Disease Progression
Nucleotides
Bone Marrow
Epithelial Cells
Morbidity

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Allen, I. C., Tekippe, E. M., Woodford, R. M. T., Uronis, J. M., Holl, E. K., Rogers, A. B., ... Ting, J. P. Y. (2010). The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. Journal of Experimental Medicine, 207(5), 1045-1056. https://doi.org/10.1084/jem.20100050

The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. / 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.

In: Journal of Experimental Medicine, Vol. 207, No. 5, 10.05.2010, p. 1045-1056.

Research output: Contribution to journalArticle

Allen, IC, Tekippe, EM, Woodford, RMT, Uronis, JM, Holl, EK, Rogers, AB, Herfarth, HH, Jobin, C & Ting, JPY 2010, 'The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer', Journal of Experimental Medicine, vol. 207, no. 5, pp. 1045-1056. https://doi.org/10.1084/jem.20100050
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. / The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. In: Journal of Experimental Medicine. 2010 ; Vol. 207, No. 5. pp. 1045-1056.
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