Article Text
Abstract
Objective Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (Ctsk−/− ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation.
Design Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk−/− mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples.
Results Using Ctsk−/− mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk−/− mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk−/− mice ameliorates the severity of intestinal inflammation.
Conclusion These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.
- Inflammatory bowel disease
- DSS colitis
- lysosomal protease
- cathepsin K knockout mouse
- chronic ulcerative colitis
- Crohn's disease
- Crohn's colitis
- bacterial infection
- bacterial pathogenesis
- infectious disease
- antibacterial peptide
- immunodeficiency
- inflammatory cells
- mucosal barrier
- small intestine
- mucosal infection
- mucus
- mucins
- gastric mucosal barrier
- enteric infections
- intestinal barrier function
- Helicobacter pylori infection
- mucosal immunity
- cytokines
- genetics
- signal transduction
- immunohistochemistry
- IBD basic research
- IBD-genetics
- antibacterial mucosal immunity
- infliximab