Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages

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 (β₂-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 β₂- 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 β₂-AR, as determined by time course experiments and the use of a specific β₂-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 β₂-AR agonists on the airways besides the desensitization of the β₂-AR.