title: Salmeterol with fluticasone enhances the suppression of IL-8 release and increases the translocation of glucocorticoid receptor by human neutrophils stimulated with cigarette smoke.
abstract: The combination of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists is increasingly used in chronic obstructive pulmonary disease (COPD). Recently, we have demonstrated that combination of salmeterol and fluticasone propionate (FP) additionally suppress the production of IL-8 by human monocyte. In this study, the molecular mechanism behind the effectiveness of this combination therapy is investigated in human neutrophils. Human neutrophils were preincubated with salmeterol or FP or the combination. The amount of interleukin-8 (IL-8), elastase and matrix metalloproteinases (MMP)-2 and -9 releases, and reactive oxygen species (ROS) generation and expression of MAP kinase phosphatase (MKP-1) and glucocorticoid receptor (GR) were determined. Cigarette smoke medium (CSM) induces an increased expression of CXC receptors and the production of ROS that may explain the strong production of IL-8 by neutrophils. The expression of CXC receptors, the production of ROS, and the release of elastase and MMP-2 and -9 were not influenced by salmeterol, FP, or the combination. Interestingly, the combination therapy had an additive suppressive effect on the CSM-induced production of IL-8. The latter could be explained by an increased mRNA expression of MKP-1, the GR and an increased translocation of the GR to the nucleus. This leads eventually to suppression of both the NF-kappaB and MAPK pathways and, hence, to less IL-8 production by the neutrophil. These data are in support for the use of a combination therapy in COPD patients.
authors.affiliation: Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands. e.mortaz@uu.nl
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Mortaz
authors.forename: Mehdi Vaezi
authors.initials: MV
authors.lastname: Rad
authors.forename: Malcolm
authors.initials: M
authors.lastname: Johnson
authors.forename: Danielle
authors.initials: D
authors.lastname: Raats
authors.forename: Frans P
authors.initials: FP
authors.lastname: Nijkamp
authors.forename: Gert
authors.initials: G
authors.lastname: Folkerts
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000730:Androstadienes / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D000068298:Fluticasone; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D000068299:Salmeterol Xinafoate; D015398:Signal Transduction / Q000502:physiology; D012906:Smoke; D014026:Nicotiana
chemical_list: D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D001993:Bronchodilator Agents; D016209:Interleukin-8; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D011965:Receptors, Glucocorticoid; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D012906:Smoke; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D020928:Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D010196:Pancreatic Elastase; D020782:Matrix Metalloproteinases; D000420:Albuterol