Abstract
The kallikrein–kinin system (KKS) consists of two serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-molecular-weight kininogen (HK). Upon activation of the KKS, HK is cleaved to release bradykinin. Although the KKS is activated in humans and animals with inflammatory bowel disease (IBD), its role in the pathogenesis of IBD has not been characterized. In the present study, we determined the role of the KKS in the pathogenesis of IBD using mice that lack proteins involved in the KKS. In two colitis models, induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS), mice deficient in HK, pKal, or bradykinin receptors displayed attenuated phenotypes, including body weight loss, disease activity index, colon length shortening, histological scoring, and colonic production of cytokines. Infiltration of neutrophils and inflammatory monocytes in the colonic lamina propria was reduced in HK-deficient mice. Reconstitution of HK-deficient mice through intravenous injection of HK recovered their susceptibility to DSS-induced colitis, increased IL-1β levels in the colon tissue and bradykinin concentrations in plasma. In contrast to the phenotypes of other mice lacking other proteins involved in the KKS, mice lacking FXII had comparable colonic inflammation to that observed in wild-type mice. The concentration of bradykinin was significantly increased in the plasma of wild-type mice after DSS-induced colitis. In vitro analysis revealed that DSS-induced pKal activation, HK cleavage, and bradykinin plasma release were prevented by the absence of pKal or the inhibition of Kal. Unlike DSS, TNBS-induced colitis did not trigger HK cleavage. Collectively, our data strongly suggest that Kal, acting independently of FXII, contributes to experimental colitis by promoting bradykinin release from HK.
Highlights
Inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC) and Crohn’s disease (CD), are debilitating disorders caused by gastrointestinal mucosal damage and inflammation
Using kallikrein–kinin system (KKS)-knockout mice in two experimental colitis models, the present study demonstrates that pKal, high-molecular-weight kininogen (HK), or combined B1R/B2R, but not factor XII (FXII), deficiency protects against colitis
The role for HK in colitis development is likely dependent on bradykinin production, as a similar phenotype was observed in B1RB2R-deficient mice
Summary
Inflammatory bowel diseases (IBDs), such as ulcerative colitis (UC) and Crohn’s disease (CD), are debilitating disorders caused by gastrointestinal mucosal damage and inflammation. IBDs are associated with a compromised gastrointestinal barrier, leading to inflammation directly through tissue injury and indirectly via the production of various proinflammatory mediators that recruit immune cells. The plasma kallikrein–kinin system (KKS) consists of a group of plasma proteins that responds to pathophysiological stimuli and tissue injury [3], two serine proteinases [coagulation factor XII (FXII) and prekallikrein (pKal)], and a non-enzymatic cofactor [high-molecular-weight kininogen (HK)] [4]. FXIIa cleaves pKal, generating Kal, which in turn activates additional FXII zymogens. Activated Kal, which is the major bradykinin-releasing enzyme in blood, cleaves HK to HKa and bradykinin, a short-lived pro-inflammatory nanopeptide [5]. PKal can be activated by the lysosomal enzyme prolylcarboxypeptidase and heat-shock protein 90 independently of FXII [6,7,8,9]. Bradykinin and des(Arg9)-bradykinin are the agonists of two G protein-coupled receptors (designated as B2R and B1R, respectively) [10, 11]
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