Caspase-11 regulates the tumour suppressor function of STAT1 in a murine model of colitis-associated carcinogenesis.

Abstract

Murine inflammatory caspase-11 has an important role in intestinal epithelial inflammation and barrier function. Activation of the non-canonical inflammasome, mediated by caspase-11, serves as a regulatory pathway for the production of the pro-inflammatory cytokines IL-1β and IL-18, and has a key role in pyroptotic cell death. We have previously demonstrated a protective role for caspase-11 during dextran sulphate sodium (DSS)-induced colitis, however the importance of caspase-11 during colorectal tumour development remains unclear. Here, we show that Casp11-/- mice are highly susceptible to the azoxymethane (AOM)-DSS model of colitis-associated cancer (CAC), compared to their wild type (WT) littermates. We show that deficient IL-18 production occurs at initial inflammation stages of disease, and that IL-1β production is more significantly impaired in Casp11-/- colons during established CAC. We identify defective STAT1 activation in Casp11-/- colons during disease progression, and show that IL-1β signalling induces caspase-11 expression and STAT1 activation in primary murine macrophages and intestinal epithelial cells. These findings uncover an anti-tumour role for the caspase-11 and the non-canonical inflammasome during CAC, and suggest a critical role for caspase-11, linking IL-1β and STAT1 signalling pathways.

• Authors: Brian Flood, Joan Manils, Ciara Nulty, Ewelina Flis, Sinead Kenealy, Gillian Barber, Joanna Fay, Kingston H G Mills, Elaine W Kay, Emma M Creagh
• Journal: Oncogene (Oncogene) Vol. 38 Issue 14 Pg. 2658-2674 (04 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 30538296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Inflammasomes
• Interleukin-1beta
• STAT1 Transcription Factor
• Stat1 protein, mouse
• Tumor Suppressor Proteins
• Casp4 protein, mouse
• Caspases
• Caspases, Initiator

Topics

• Animals
• Carcinogenesis (metabolism, pathology)
• Caspases (metabolism)
• Caspases, Initiator
• Cell Line, Tumor
• Colitis (metabolism, pathology)
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Inflammasomes (metabolism)
• Inflammation (metabolism, pathology)
• Interleukin-1beta (metabolism)
• Mice
• Mice, Inbred C57BL
• STAT1 Transcription Factor (metabolism)
• Signal Transduction (physiology)
• Tumor Suppressor Proteins (metabolism)