title: Corticosteroids inhibit sphingosine 1-phosphate-induced interleukin-6 secretion from human airway smooth muscle via mitogen-activated protein kinase phosphatase 1-mediated repression of mitogen and stress-activated protein kinase 1.
abstract: Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that plays an important proinflammatory role in asthmatic airways. Corticosteroids are first-line antiinflammatories in asthma; however, their repressive effects on S1P-induced cytokine secretion have not been investigated. To address this, our in vitro study reveals the molecular mechanisms by which corticosteroids inhibit S1P-induced IL-6 expression in the pivotal immunomodulatory cell type, airway smooth muscle (ASM). We first uncover the cellular signaling pathways responsible: S1P activates a cyclic adenosine monophosphate/cAMP response-element-binding protein (CREB)/CRE-dependent pathway to induce IL-6 transcription, concomitant with stimulation of the mitogen-activated protein kinase (MAPK) superfamily and downstream mitogen and stress-activated protein kinase 1 (MSK1) and histone H3 phosphorylation. In this way, S1P stimulates parallel signaling pathways to induce IL-6 secretion via CRE-driven transcription of the IL-6 gene promoter in a relaxed chromatin environment achieved through histone H3 phosphorylation. Second, we investigated how corticosteroids mediate their repressive effects. The corticosteroid dexamethasone inhibits S1P-induced IL-6 protein secretion and mRNA expression, but CREB/CRE transrepression, inhibition of IL-6 mRNA stability, or subcellular relocation of MSK1 were not responsible for the repressive effects of dexamethasone. Rather, we show that dexamethasone rapidly induces up-regulation of the MAPK deactivator MAPK phosphatase 1 (MKP-1) and that MKP-1 blocks the MAPK-driven activation of MSK1 and phosphorylation of histone H3. This was confirmed by treatment with triptolide, an inhibitor of MKP-1 up-regulation, where repressive effects of corticosteroids were reversed. Our study reveals the molecular mechanism underlying the antiinflammatory capacity of corticosteroids to repress proinflammatory functions induced by the potent bioactive sphingolipid S1P in the lung.
authors.affiliation: 1 Respiratory Research Group, Faculty of Pharmacy, and.
authors.forename: Wenchi
authors.initials: W
authors.lastname: Che
authors.forename: Johannes
authors.initials: J
authors.lastname: Parmentier
authors.forename: Petra
authors.initials: P
authors.lastname: Seidel
authors.forename: Melanie
authors.initials: M
authors.lastname: Manetsch
authors.forename: Emma E
authors.initials: EE
authors.lastname: Ramsay
authors.forename: Hatem
authors.initials: H
authors.lastname: Alkhouri
authors.forename: Qi
authors.initials: Q
authors.lastname: Ge
authors.forename: Carol L
authors.initials: CL
authors.lastname: Armour
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D054638:Dual Specificity Phosphatase 1 / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D017362:Cyclic AMP Response Element-Binding Protein; C508600:IL6 protein, human; D015850:Interleukin-6; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D000242:Cyclic AMP; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054638:Dual Specificity Phosphatase 1; D013110:Sphingosine