Interleukin‐4 increases murine airway response to kinins, via up‐regulation of bradykinin B₁‐receptors and altered signalling along mitogen‐activated protein kinase pathways

<jats:title>Summary</jats:title><jats:p><jats:bold>Background </jats:bold> IL‐4 is believed to play a role in asthma and chronic obstructive pulmonary disease through promotion of eosinophilic inflammation and mucus hypersecretion. Whether IL‐4 can induce a direct effect on airway smooth muscle remains unknown.</jats:p><jats:p><jats:bold>Objective </jats:bold> To investigate the effect of IL‐4 on airway smooth muscle, focusing on the contractile response to des‐Arg<jats:sup>9</jats:sup>‐bradykinin and bradykinin.</jats:p><jats:p><jats:bold>Methods </jats:bold> Tracheal segments from murine airways were cultured for 1–8 days in the absence and presence of IL‐4. The smooth muscle response induced by des‐Arg<jats:sup>9</jats:sup>‐bradykinin and bradykinin was investigated in myographs. Expression levels for the IL‐4‐, bradykinin B<jats:sub>1</jats:sub>‐ and B<jats:sub>2</jats:sub>‐receptors were characterized using RT‐PCR. Specific inhibitors were used to study signal changes along the IL‐4 receptor‐ (IL‐4R‐) coupled mitogen‐activated protein (MAP) kinase (MAPK) pathways.</jats:p><jats:p><jats:bold>Results </jats:bold> IL‐4 treatment increased the contractile response to des‐Arg<jats:sup>9</jats:sup>‐bradykinin and bradykinin in a concentration‐ and time‐dependent manner. Dexamethasone and the transcriptional inhibitor actinomycin D blocked this effect. c‐Jun N‐terminal kinase inhibitor SP600125 also blocked the effect of both des‐Arg<jats:sup>9</jats:sup>‐bradykinin and bradykinin, whereas p38 inhibitor SB203580 blocked only the former and the MAPKK inhibitor PD098059, only the latter agonist responses. IL‐4 treatment increased the mRNA levels representing bradykinin B<jats:sub>1</jats:sub>‐ but not B<jats:sub>2</jats:sub>‐receptors. Levels of IL‐4R were not altered during culture.</jats:p><jats:p><jats:bold>Conclusion </jats:bold> Long‐term exposure to IL‐4 increases the contractile response induced by des‐Arg<jats:sup>9</jats:sup>‐bradykinin and bradykinin in cultured murine airways. This effect appears to be mediated via an up‐regulation of B<jats:sub>1</jats:sub>‐receptors and altered signalling along the MAPK pathways.</jats:p>