title: Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages.
abstract: Vascular endothelial growth factor (VEGF), oncostatin M (OSM), and granulocyte chemotactic protein-2 (GCP-2/CXCL6) are up-regulated in U937 macrophages and peripheral blood macrophages exposed to LPS, beta-adrenergic receptor (beta2-AR) agonists (e.g. zilpaterol, and clenbuterol) and some other agents that induce intracellular cAMP (prostaglandin E2, forskolin, and butyryl cAMP). LPS in combination with beta2-agonists and cAMP elevating agents had an additional effect on the release of VEGF, OSM, and CXCL6. These proteins are up-regulated after 16-24 h of exposure and this is mediated by the beta2-AR, as determined by time course experiments and the use of a specific beta2-AR antagonist (ICI 118551). Beta2-AR agonists are used as bronchodilators in the treatment of asthma, but appear to have no effect on the chronic inflammation of the disease. However, the up-regulation of VEGF, OSM, and CXCL6 may have adverse effects on the inflammatory process of asthma. These mediators are involved in the recruitment of neutrophils, airway remodelling and angiogenesis, known features of chronic inflammatory diseases. We propose that the up-regulation of these proteins could play a role in the adverse effects of prolonged excessive usage of beta2-AR agonists on the airways besides the desensitization of the beta2-AR.
authors.affiliation: TNO Pharma, Utrechtseweg 48, P.O. Box 360, 3700AJ Zeist, The Netherlands Verhoeckx@pharma.tno.nl
authors.forename: Kitty C M
authors.initials: KC
authors.lastname: Verhoeckx
authors.forename: Robert P
authors.initials: RP
authors.lastname: Doornbos
authors.forename: Renger F
authors.initials: RF
authors.lastname: Witkamp
authors.forename: Jan
authors.initials: J
authors.lastname: van der Greef
authors.forename: Richard J T
authors.initials: RJ
authors.lastname: Rodenburg
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D054427:Chemokine CXCL6; D019743:Chemokines, CXC / Q000096:biosynthesis*; D002976:Clenbuterol / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D053683:Oncostatin M; D014297:Trimethylsilyl Compounds / Q000494:pharmacology; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D000318:Adrenergic beta-Agonists; C515503:CXCL6 protein, human; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; D016207:Cytokines; D008070:Lipopolysaccharides; C508351:OSM protein, human; D014297:Trimethylsilyl Compounds; D042461:Vascular Endothelial Growth Factor A; C475840:Zilpaterol; D053683:Oncostatin M; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; D015232:Dinoprostone; D002976:Clenbuterol