Exacerbation of DSS-induced colitis in mice lacking kinin B-1 receptors through compensatory up-regulation of kinin B-2 receptors: the role of tight junctions and intestinal homeostasis

BACKGROUND AND PURPOSE Kinins are pro-inflammatory peptides that are released during tissue injury, including that caused by inflammatory bowel disease. Herein, we assessed the role and underlying mechanisms through which the absence of kinin B-1 receptors exacerbates the development of dextran sulfate sodium (DSS)-induced colitis in mice. EXPERIMENTAL APPROACH B-1 and B-2 receptor antagonists and B-1 receptor knockout mice (B1(-/-)) were used to assess the involvement of B-1 and B-2 receptor signalling in a DSS-colitis. B1 receptor, B2 receptor, occludin and claudin-4 expression, cytokine levels and cell permeability were evaluated in colon from wild-type (WT) and B1(-/-) mice. KEY RESULTS DSS-induced colitis was significantly exacerbated in B1(-/-) compared with WT mice. IL-1 beta, IFN-gamma, keratinocyte-derived chemokine and macrophage inflammatory protein-2 were markedly increased in the colon from DSS-treated B1(-/-) compared with DSS-treated WT mice. Treatment of WT mice with a selective B-1 receptor antagonist, DALBK or SSR240612, had no effect on DSS-induced colitis. Of note, B-2 receptor mRNA expression was significantly up-regulated in colonic tissue from the B1(-/-) mice after DSS administration. Moreover, treatment with a selective B2 receptor antagonist prevented the exacerbation of colitis in B1(-/-) mice following DSS administration. The water- or DSS-treated B1(-/-) mice showed a decrease in occludin gene expression, which was partially prevented by the B2 receptor antagonist. CONCLUSIONS AND IMPLICATIONS A loss of B-1 receptors markedly exacerbates the severity of DSS-induced colitis in mice. The increased susceptibility of B1(-/-) may be associated with compensatory overexpression of B-2 receptors, which, in turn, modulates tight junction expression.