Exacerbation of DSS-induced colitis in mice lacking kinin B1 receptors through compensatory up-regulation of kinin B2 receptors: the role of tight junctions and intestinal homeostasis

Authors


Correspondence

João B Calixto, Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina 88049-900, Brazil. E-mail: calixto@farmaco.ufsc.br; calixto3@terra.com.br

Abstract

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 B1 receptors exacerbates the development of dextran sulfate sodium (DSS)-induced colitis in mice.

Experimental Approach

B1 and B2 receptor antagonists and B1 receptor knockout mice (B1−/−) were used to assess the involvement of B1 and B2 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-1β, IFN-γ, 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 B1 receptor antagonist, DALBK or SSR240612, had no effect on DSS-induced colitis. Of note, B2 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 B1 receptors markedly exacerbates the severity of DSS-induced colitis in mice. The increased susceptibility of B1−/− may be associated with compensatory overexpression of B2 receptors, which, in turn, modulates tight junction expression.

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