title: Sphingosine 1-phosphate induces neutrophil chemoattractant IL-8: repression by steroids.
abstract: The bioactive sphingolipid sphingosine 1-phosphate (S1P) is found in increased amounts in the airways of asthmatics. S1P can regulate airway smooth muscle functions associated with asthmatic inflammation and remodeling, including cytokine secretion. To date however, whether S1P induces secretion of an important chemokine responsible for neutrophilia in airway inflammation--IL-8--was unexplored. The aim of this study was to investigate whether S1P induces IL-8 gene expression and secretion to enhance neutrophil chemotaxis in vitro, as well as examine the molecular mechanisms responsible for repression by the corticosteroid dexamethasone. We show that S1P upregulates IL-8 secretion from ASM cells and enhance neutrophil chemotaxis in vitro. The corticosteroid dexamethasone significantly represses IL-8 mRNA expression and protein secretion in a concentration- and time-dependent manner. Additionally, we reveal that S1P-induced IL-8 secretion is p38 MAPK and ERK-dependent and that these key phosphoproteins act on the downstream effector mitogen- and stress-activated kinase 1 (MSK1) to control secretion of the neutrophil chemoattractant cytokine IL-8. The functional relevance of this in vitro data was demonstrated by neutrophil chemotaxis assays where S1P-induced effects can be significantly attenuated by pretreatment with dexamethasone, pharmacological inhibition of p38 MAPK- or ERK-mediated pathways, or by knocking down MSK-1 with siRNA. Taken together, our study reveals the molecular pathways responsible for IL-8 secretion from ASM cells in response to S1P and indicates ways in which the impact on IL-8-driven neutrophilia may be lessened.
authors.affiliation: Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: Md Mostafizur
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: Hatem
authors.initials: H
authors.lastname: Alkhouri
authors.affiliation: Woolcock Institute of Medical Research, University of Sydney, New South Wales, Australia.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tang
authors.affiliation: Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: Wenchi
authors.initials: W
authors.lastname: Che
authors.affiliation: Woolcock Institute of Medical Research, University of Sydney, New South Wales, Australia.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ge
authors.affiliation: Faculty of Pharmacy, University of Sydney, New South Wales, Australia.
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
mesh_terms: D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016209:Interleukin-8; D008246:Lysophospholipids; D016328:NF-kappa B; C060506:sphingosine 1-phosphate; D013110:Sphingosine