title: Differential modulation of glucocorticoid action by FK506 in A549 cells.
abstract: Glucocorticoids inhibit the release of eicosanoid pro-inflammatory mediators. The immunosuppressant FK506 is known to enhance many aspects of glucocorticoid action. In the present study we show that FK506 (1 microM or 10 microM) inhibits the release of arachidonic acid and prostaglandin E2 from A549 cells and also inhibits their proliferation. Simultaneous treatment of FK506 together with the glucocorticoids dexamethasone, methyl-prednisolone, fluticasone or mometasone (10 nM) enhances the growth inhibitory effect of these steroids. Furthermore, the simultaneous use of FK506 and these glucocorticoids similarly results in enhanced inhibition of arachidonic acid release. When pretreated for 2 h, FK506 enhances glucocorticoid inhibition of COX2 (cyclo-oxygenase 2) expression. However, when administered simultaneously, FK506 blocks glucocorticoid inhibition of COX2 expression. Nuclear uptake of glucocorticoid receptors mediated by glucocorticoids is also blocked by the simultaneous administration of FK506. These results suggest that the effect of simultaneous treatment of FK506 with glucocorticoids differs significantly from that where pre-treatment of the immunosuppressant is used. Recently, immunophilin interchange has been identified as a first step in glucocorticoid receptor activation following ligand activation. We show here that the FKB51 (FK506-binding protein 51)-FKB52 switch is differentially regulated by glucocorticoid and FK506 treatment strategy.
authors.affiliation: Department of Biochemical Pharmacology, William Harvey Research Institute, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK. J.Croxtall@qmul.ac.uk
authors.forename: Jamie D
authors.initials: JD
authors.lastname: Croxtall
authors.forename: Mark
authors.initials: M
authors.lastname: Paul-Clark
authors.forename: Peter Th W
authors.initials: PT
authors.lastname: Van Hal
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004357:Drug Synergism; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D008565:Membrane Proteins; D011965:Receptors, Glucocorticoid; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D022021:Tacrolimus Binding Proteins; D015232:Dinoprostone; D016559:Tacrolimus