Glucocorticoids ablate IL-1β-induced β-adrenergic hyporesponsiveness in human airway smooth muscle cells

We have previously reported that interleukin (IL)-1 beta decreases responsiveness of cultured human airway smooth muscle (HASM) cells to beta-agonists. The purpose of this study was to determine whether glucocorticoids inhibit this IL-1 beta effect. Dexamethasone (Dex; 10(-6) M) had no effect on concentration-related decreases in cell stiffness in response to isoproterenol (Iso) in control cells as measured by magnetic twisting cytometry but prevented the decreased responsiveness to Iso observed in IL-1 beta (20 ng/ml)-treated cells. In addition, Dex had no effect on Iso-stimulated cAMP formation in control cells but prevented the IL-1 beta-induced reduction in Iso-stimulated cAMP formation. Similar effects on cell stiffness and cAMP responses were seen after pretreatment with the glucocorticoid fluticasone proprionate (FP). Dex and FP also prevented IL-1 beta-induced hyporesponsiveness to PGE(2) stimulation. In contrast, neither IL-1 beta nor glucocorticoids had any effect on cell stiffness responses to dibutyryl cAMP. We have previously reported that the IL-1 beta effect on beta-adrenergic responsiveness is mediated through cyclooxygenase-2 expression and prostanoid formation. Consistent with these observations, IL-lp-induced cyclooxygenase-2 expression was virtually abolished by FP at concentrations of 10(-10) M and greater, with a resultant decrease in PGE2 formation. However, Dex did not inhibit IL-1 beta-induced nuclear translocation of nuclear factor-kappa B or activator protein-1 in HASM cells. In summary, our results indicate that, in HASM cells, glucocorticoids alone do not alter responses to beta-agonists but do inhibit IL-1 beta-induced beta-adrenergic hyporesponsiveness. Glucocorticoids mediate this effect by inhibiting prostanoid formation but without altering nuclear factor-kappa B or activator protein-1 translocation.