title: Inhibition by salmeterol and cilomilast of fluticasone-enhanced IP-10 release in airway epithelial cells.
abstract: The CXC chemokines, IP-10/CXCL10 and IL-8/CXCL8, play a role in obstructive lung disease by attracting Th1/Tc1 lymphocytes and neutrophils, respectively. Inhaled corticosteroids (ICS) and long acting beta 2-agonists (LABA) are widely used. However, their effect(s) on the release of IP-10 and IL-8 by airway epithelial cells are poorly understood. This study examined the effects of fluticasone, salmeterol, and agents which raise intracellular cAMP (cilomilast and db-cAMP) on the expression of IP-10 and IL-8 protein and mRNA. Studies were performed in cultured human airway epithelial cells during cytokine-stimulated IP-10 and IL-8 release. Cytokine treatment (TNF-alpha, IL-1beta and IFN-gamma) increased IP-10 and IL-8 protein and mRNA levels. Fluticasone (0.1 nM to 1 microM) increased IP-10 but reduced IL-8 protein release without changing IP-10 mRNA levels assessed by real time RT-PCR. The combination of salmeterol (1 micro M) and cilomilast (1-10 mu M) reduced IP-10 but had no effect on IL-8 protein. Salmeterol alone (1 micro M) and db-cAMP alone (1 mM) antagonised the effects of fluticasone on IP-10 but not IL-8 protein. In human airway epithelial cells, inhibition by salmeterol of fluticasone-enhanced IP-10 release may be an important therapeutic effect of the LABA/ICS combination not present when the two drugs are used separately.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Temple University Hospital, Philadelphia, PA 19140, USA. pjreddy2@yahoo.com
authors.forename: P J
authors.initials: PJ
authors.lastname: Reddy
authors.forename: Mark O
authors.initials: MO
authors.lastname: Aksoy
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiu Xia
authors.initials: XX
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Ji
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kelsen
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002264:Carboxylic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D003509:Cyclohexanecarboxylic Acids; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors; D012313:RNA / Q000235:genetics*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068299:Salmeterol Xinafoate
chemical_list: D000318:Adrenergic beta-Agonists; D002264:Carboxylic Acids; D054357:Chemokine CXCL10; D003509:Cyclohexanecarboxylic Acids; D016209:Interleukin-8; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D012313:RNA; D000068299:Salmeterol Xinafoate; C433247:Cilomilast; D000420:Albuterol