p38 MAP kinase regulates IL-1β responses in cultured airway smooth muscle cells

Abstract

We have previously reported that interleukin (IL)-1β causes β-adrenergic hyporesponsiveness in cultured human airway smooth muscle (HASM) cells by increasing cyclooxygenase (COX)-2 expression. The purpose of this study was to determine whether p38 mitogen-activated protein (MAP) kinase is involved in these events. IL-1β (2 ng/ml for 15 min) increased p38 phosphorylation fourfold. The p38 inhibitor SB-203580 (3 μM) decreased IL-1β-induced COX-2 by 70 ± 7% (P < 0.01). SB-203580 had no effect on PGE2 release in control cells but caused a significant (70-80%) reduction in PGE2 release in IL-1β-treated cells. IL-1β increased the binding of nuclear proteins to the oligonucleotides encoding the consensus sequences for activator protein (AP)-1 and nuclear factor (NF)-κB, but SB-203580 did not affect this binding, suggesting that the mechanism of action of p38 was not through AP-1 or NF-κB activation. The NF-κB inhibitor MG-132 did not alter IL-1β-induced COX-2 expression, indicating that NF-κB activation is not required for IL-1β-induced COX-2 expression in HASM cells. IL-1β attenuated isoproterenol-induced decreases in HASM stiffness as measured by magnetic twisting cytometry, and SB-203580 abolished this effect. These results are consistent with the hypothesis that p38 is involved in the signal transduction pathway through which IL-1β induces COX-2 expression, PGE2 release, and β-adrenergic hyporesponsiveness.