Intestinal tissue kallikrein-kinin system in inflammatory bowel disease

Abstract

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.

MAPK/NF-κB-dependent upregulation of kinin receptors mediates airway hyperreactivity: A new perspective for the treatment

“…Bradykinin and related kinins are produced from both blood (plasma kallikrein-kinin system) and tissues (tissue kallikreinkinin system) in response to inflammatory stimuli [87,88]. Bradykinin is a nine amino acid peptide (Arg-Pro-Pro-Gly-PheSer-Pro-Phe-Arg), formed from the kininogen precursor after proteolytic cleavage by tissue and plasma kallikrein.…”

Effects of a marine serine protease inhibitor on viability and morphology of Trypanosoma cruzi, the agent of Chagas disease

“…The highest inhibitory effect can be observed in the activity of the extracellular serine peptidase (IC 50 about 8.8-4.06 × 10 −8 M, Table 2b). Similar ShPI-I inhibition could be observed for another serine peptidase that acts in the extracellular environment, tissue kallikrein (Delfin et al, 1996), that cleaves kininogens to release kinins secreted by exocrine glands (Stadnicki, 2011). It is known that T. cruzi epimastigote secretes two serine peptidases into the extracellular milieu (Santana et al, 1997;Silva-López et al, 2008).…”

Bifidobacterium bifidum PRL2010 Modulates the Host Innate Immune Response

“…Intestinal kallikrein may degrade growth factors and peptides, whereas kinins are responsible for capillary permeability, pain, synthesis of cytokines, and the adhesion molecule neutrophil cascade. Recent studies have shown that kallikrein is present in intestinal goblet cells and is released into interstitial space during inflammation (74).…”