Participation of beta-adrenergic receptors on macrophages in modulation ofLPS-induced cytokine release

For several years it is known that beta-adrenergic receptor agonists have a ntiinflammatory effects. However, little is known about the role of beta-ad renergic receptors on macrophages in the modulation of cytokine production by beta-agonists during inflammation. In this study, the presence of beta-r eceptors on PMA-differentiated U937 human macrophages, and the participatio n of these receptors in the modulation of LPS-mediated cytokine production by beta-agonists was investigated. Total beta-receptor expression on undiff erentiated (monocyte) and PMA-differentiated U937 cells was established usi ng receptor binding studies on membrane fractions with a radio ligand. The expression of beta-receptors proved to be significantly lower on monocytes than on macrophages, additionally a predominant expression of beta 2-recept ors was found. Production of the cytokines TNF-alpha, IL-6, and IL-10 by LP S-stimulated differentiated U937 cells was measured in time. Peak concentra tions for TNF-alpha, IL-6 and IL-10 occurred at 3, 12 and 9 hrs, respective ly. When differentiated U937 cells were incubated with both LPS and the bet a-agonist clenbuterol the production of TNF-alpha and IL-6 was significantl y reduced. However the production of IL-10 was increased. To study the mech anism of modulation of cytokine production in more detail, U937 macrophages were incubated with LPS/clenbuterol in combination with selective beta 1- and beta 2- antagonists. These results indicated that the beta 2- and not t he beta 1-receptor is involved in the anti-inflammatory activity of clenbut erol.