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

Background 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. Objective To investigate the effect of IL-4 on airway smooth muscle, focusing on the contractile response to des-Arg(9)-bradykinin and bradykinin. Methods 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(9)-bradykinin and bradykinin was investigated in myographs. Expression levels for the IL-4-, bradykinin B-1- and B-2-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. Results IL-4 treatment increased the contractile response to des-Arg(9)-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(9)-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-1- but not B-2-receptors. Levels of IL-4R were not altered during culture. Conclusion Long-term exposure to IL-4 increases the contractile response induced by des-Arg(9)-bradykinin and bradykinin in cultured murine airways. This effect appears to be mediated via an up-regulation of B-1-receptors and altered signalling along the MAPK pathways.