title: Glucocorticoids ablate IL-1beta-induced beta-adrenergic hyporesponsiveness in human airway smooth muscle cells.
abstract: We have previously reported that interleukin (IL)-1beta 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-1beta 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-1beta (20 ng/ml)-treated cells. In addition, Dex had no effect on Iso-stimulated cAMP formation in control cells but prevented the IL-1beta-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-1beta-induced hyporesponsiveness to PGE(2) stimulation. In contrast, neither IL-1beta nor glucocorticoids had any effect on cell stiffness responses to dibutyryl cAMP. We have previously reported that the IL-1beta effect on beta-adrenergic responsiveness is mediated through cyclooxygenase-2 expression and prostanoid formation. Consistent with these observations, IL-1beta-induced cyclooxygenase-2 expression was virtually abolished by FP at concentrations of 10(-10) M and greater, with a resultant decrease in PGE(2) formation. However, Dex did not inhibit IL-1beta-induced nuclear translocation of nuclear factor-kappaB 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-1beta-induced beta-adrenergic hyporesponsiveness. Glucocorticoids mediate this effect by inhibiting prostanoid formation but without altering nuclear factor-kappaB or activator protein-1 translocation.
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: P E
authors.initials: PE
authors.lastname: Moore
authors.forename: J D
authors.initials: JD
authors.lastname: Laporte
authors.forename: S
authors.initials: S
authors.lastname: Gonzalez
authors.forename: W
authors.initials: W
authors.lastname: Moller
authors.forename: J
authors.initials: J
authors.lastname: Heyder
authors.forename: R A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: S A
authors.initials: SA
authors.lastname: Shore
mesh_terms: D001993:Bronchodilator Agents / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis; D007545:Isoproterenol / Q000494:pharmacology; D008280:Magnetics; D008565:Membrane Proteins; D008863:Microspheres; D009130:Muscle, Smooth / Q000737:chemistry* / Q000201:enzymology / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000096:biosynthesis; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D014132:Trachea / Q000737:chemistry* / Q000166:cytology / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D001993:Bronchodilator Agents; D005938:Glucocorticoids; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D011943:Receptors, Adrenergic, beta; D018808:Transcription Factor AP-1; D003994:Bucladesine; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007545:Isoproterenol