Altered expression of inflammatory caspases during inflammatory bowel disease and colorectal cancer.
B. Flood1, K. Oficjalska1, D. Laukens2, J. Fay3, K.H.G. Mills1, K. Sheahan4, E.J. Ryan4, G.A. Doherty4, E. Kay3 and E.M. Creagh1.
1School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland; 2Department of Gastroenterology, Ghent University, Belgium; 3RCSI and Beaumont Hospital, Dublin.
Caspases are a group of proteolytic enzymes involved in the co-ordination of cellular processes, including cellular homeostasis, inflammation and apoptosis. Altered activity of caspases, particularly caspase-1, has been implicated in the development of intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, the involvement of two related inflammatory caspase members, human caspases-4 and -5 (or their murine equivalent, caspase-11) during intestinal homeostasis and disease has not yet been established.
This study aimed to characterise the involvement of inflammatory caspases during IBD and CRC.
IHC techniques were employed to examine the cellular expression levels of Inflammatory Caspases in ulcerative colitis (UC) and CRC patients (both sporadic and UC-associated CRC) at various stages of disease severity. Experimental models of acute colitis (elicited by dextran sodium sulfate (DSS)) and CRC (elicited by azoxymethane (AOM) and DSS) were also performed in control and caspase-11 deficient mice, to determine the importance of caspase-11 (the caspase-4/-5 equivalent in mice) during these disease models.
Increased expression of caspases-4 and -5 in infiltrating immune cells strongly correlated with inflammation scores and disease activity in UC patients. In CRC patients, caspases-4 and -5 were selectively expressed in malignant epithelial cells. Examination of adjacent-normal, inflamed and tumour tissue confirmed that epithelial expression is specific to neoplastic tissue. Murine studies revealed that caspase-11 is protective during experimental models of UC and UC-associated CRC.
This study identifies epithelial-expressed caspases- 4 and -5 as novel biomarkers for CRC. It also identifies caspases-4 and -5 as potential targets for the therapeutic regulation of intestinal inflammation.