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-Arg9-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-Arg9-bradykinin and bradykinin was investigated in myographs. Expression levels for the IL-4-, bradykinin B1- and B2-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-Arg9-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-Arg9-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 B1- but not B2-receptors. Levels of IL-4R were not altered during culture.


CONCLUSIONS
Long-term exposure to IL-4 increases the contractile response induced by des-Arg9-bradykinin and bradykinin in cultured murine airways. This effect appears to be mediated via an up-regulation of B1-receptors and altered signalling along the MAPK pathways.
Laboratory of Clinical and Experimental Allergy, Department of Otorhinolaryngology, Malmö University Hospital, Lund University, Malmö, Sweden. malin.bryborn@oron.mas.lu.se
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D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004576:Electromyography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000276:immunology*; D011725:Pyridines / Q000494:pharmacology; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014132:Trachea / Q000276:immunology*
D000873:Anthracenes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; C024626:bradykinin, des-Arg(9)-; D003609:Dactinomycin; C432165:pyrazolanthrone; D015847:Interleukin-4; D003907:Dexamethasone; C093642:SB 203580; D001920:Bradykinin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one