Chronic inflammation increases the risk of developing cancer. For example, patients with severe and prolonged inflammatory bowel disease, particularly ulcerative colitis, have a significantly higher risk of developing colorectal cancer. Serine proteases coordinating the coagulation cascade and immune cell proteases play important roles in regulating the inflammatory response through their actions on protease-activated receptors (PAR). PARs and their activating proteases have also been implicated in many cancers, including CRC. Importantly, the actions of proteases could be important for mediating the transition from chronic inflammation to cancer. PAR activation has been shown to have pro-tumourigenic effects including the production of matrix metalloproteinases that can promote tumour cell growth and metastasis, and transactivation of the epidermal growth factor receptor, which is a main target for cancer treatment. Additionally, PAR activation can also result in increased expression of cyclooxygenase (COX)-2, an important enzyme mediating inflammation, resolution, and cancer progression. In this review, we will highlight our current knowledge about the effects of proteases and their receptors on intestinal inflammation and cancer, and explore the potential role of PAR-induced COX-2 on colitis-associated cancer.
The MUC2 mucus layer is the first line of host defense in the gut. How MUC2 interacts with antimicrobial peptides in host defense is not well understood. In this study we investigated the interactions between MUC2 and β‐defensin. Of the colonic cells tested, β‐ defensin 2 expressions was the highest in MUC2 producing human LS 174T and the lowest in Caco‐2 cells. Similarly, expression of murine β‐defensin 4 (orthologous to human β‐defensin 2) was low in the colon of Muc2−/−mice as compared to Wt. Purified MUC2 attenuated the stimulation of β‐defensin as IL‐1β and sodium butyrate induced the expression of β‐defensin in Caco‐2, but not LS 174T cells. The antimicrobial activity of β‐defensin 2 differed among enteric bacteria; Escherichia coli were more susceptible than Bacteroides vulgatus and Clostridium difficile in killing assays. Our studies revealed that MUC2 served as a food source for enteric bacteria, which explains why Muc2−/− harbored less commensal Bacteroides and Firmicutes spp. Mechanistically, MUC2 N‐ and O‐linked oligosaccharides bound bacteria and protected them against β‐defensin 2 antimicrobial activities. MUC2 protected the microbiota by serving as a food source and by inhibiting the antimicrobial activity of β‐defensin. When the mucus barrier is compromised, β‐defensin kills susceptible bacteria whereas β‐defensin resistant bacteria may colonize and cause disease.
The intestinal epithelium is layered by a barrier composed of MUC2 mucin produced by goblet cells and β‐defensin 2, an inducible peptide produced by epithelial cells that exhibits antimicrobial and chemotactic activity. Bacteria infections and Ulcerative colitis and Crohn's diseases are associated with less MUC2 and altered defensin expression. In this study, we quantified the interaction between MUC2 mucin and β‐defensins. Human colonic mucin co‐incubated with β‐defensin 2 impaired defensin antimicrobial activities against Escherichia coli. However, addition of mucin 10–30 minutes following bacterial incubation with β‐defensin 2 did not alter antimicrobial activity. Mucin protective function on bacteria was partially abrogated by digesting the mucin terminal sialic acid residues with neuraminidases and oxidizing carbohydrate residues with sodium metaperiodate. Expression of murine β‐defensin 4 mRNA, an orthologue of human β‐defensin 2, was constitutively increased in the colons of mice deficient in MUC2 (Muc2−/−) and in dextran sodium sulfate induced colitis. These studies suggest that MUC2 abrogates the antimicrobial effect of β‐defensin in the intestinal mucosa by binding bacteria and therefore, mucin may shape the normal microflora by limiting β‐defensin antimicrobial activity. In contrast, β‐defensins are up regulated during mucosal damage when the mucus barrier is breached.
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