Anti-inflammatory effect of β2-agonists:: Inhibition of TNF-α release from human mast cells

beta(2)-Agonists inhibit the release of preformed mediators such as histamine and newly synthesized mediators such as prostaglandin D-2 from mast cells. However, although mast cells have been identified as an important source of several cytokines including tumor necrosis factor-alpha (TNF-alpha), there is no information about their regulation by beta(2)-agonists. Thus given the importance of TNF-alpha in inflammation and the widespread use of beta(2)-agonists, we investigated the effect of long-acting (salmeterol) and short-acting (salbutamol) beta(2)-agonists on the secretion of TNF-alpha from human skin mast cells. Treatment of mast cells with salmeterol or salbutamol (100 nmol/L) inhibited the IgE-dependent release of TNF-alpha (82% and 74%, respectively). Moreover, 2-hour treatment with salmeterol, isoproterenol, or salbutamol inhibited mast cell cytotoxicity against a TNF-alpha-sensitive cell line, WEHI-164, with an IC50 of 71, 50, and 29 nmol/L, respectively. Specificity for beta-adrenergic receptors was shown with propranolol. The inhibitory effect of beta(2)-agonists was observed after only 20 minutes of treatment but was lost by 24 hours after removal of salbutamol and isoproterenol (7% and 11% inhibition remaining, respectively). In contrast, the inhibition of TNF-alpha release was increased 1 hour after removal of salmeterol and remained significant 24 hours later. Furthermore, beta(2)-agonists did not show tachyphylaxis for the inhibition of TNF-alpha release. Thus selective beta(2)-agonists demonstrate anti-inflammatory activity by inhibiting the release of TNF-alpha from mast cells stimulated through their IgE receptor or by a tumor target cell. This inhibitory effect of beta-agonists may be important in their mode of action in the treatment of allergic diseases.