Intestinal tissue kallikrein-kinin system in inflammatory bowel disease.
Tissue kallikrein cleaves kininogens to release kinins. Kinins mediate inflammation by activating constitutive bradykinin receptor-2 (BR2), which are rapidly desensitized, and induced by inflammatory cytokines bradykinin receptor-1 (BR1), resistant to desensitization. Intestinal tissue kallikrein (ITK) may hydrolyze growth factors and peptides, whereas kinins are responsible for capillary permeability, pain, synthesis of cytokines, and adhesion molecule-neutrophil cascade. Our and others results have demonstrated ITK in intestinal goblet cells and its release into interstitial space during inflammation. Kallistatin, an inhibitor of ITK, has been shown in epithelial and goblet cells, and was decreased in inflamed intestine as well as in plasma compared with noninflammatory controls. BR1 was upregulated in patients with inflammatory bowel disease (IBD), and it has expressed in an apical part of enterocytes in inflamed intestine, but in the basal part in normal intestine. ITK and BR1 were visualized in macrophages forming granuloma in Crohn's disease. In animal studies BR2 blockade decreased intestinal contraction, but had limited effect on inflammatory lesions. BR1 was found to be upregulated in animal inflamed intestine, in part dependent on tumor necrosis factor alpha (TNF-α). A selective BR1 receptor antagonist decreased morphological and biochemical features of experimental intestinal inflammation. Both BR1 and BR2 mediate epithelial ion transport that leads to secretory diarrhea. The upregulation of BR1 in inflamed intestine provides a structural basis for the kinins function, suggesting that a selective BR1 antagonist may have potential in therapeutic trial of IBD patients.
Stadnicki
Antoni
A
Department of Basis Biomedical Sciences, Medical University of Silesia, Katowice, Poland. astadnic@wp.pl
D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism*; D016234:Kallikrein-Kinin System / Q000502:physiology*