Stereoselectivity at the β2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of β2-agonists

Previous research has shown that beta-adrenoceptor (P-AR) agonists have potent anti-inflammatory capabilities, e.g. represented by suppression of release of the proinflammatory cytokines. Aim of this research was to determine whether the effects of beta-agonists on LPS-induced TNF alpha and IL-10 release are influenced by their different stereochemistry. In addition, the role of the beta-AR subtypes was studied. The effect of two stereoisomers of the selective beta(2)-AR agonist TA2005 [(R,R)- and (S,S)-] on the LPS-induced TNFa and IL-IO release by U937 macrophages was compared. The (R,R)-stereoisomer was 277 times more potent in inhibiting the TNFa release than the (S,S)-form. The (R,R)stereoisomer also appeared to be more potent in increasing the IL-IO release. In radioligand binding studies the affinity of (R,R)-TA2005 for the beta-adrenoceptor was 755 times higher than the (S,S)-TA2DOS stereoisomer. In addition, the elevation of intracellular cAMP in U937 cells appeared to be stereoselective: (R,R)-TA2005 was more potent in elevating intracellular cAMP. The effect of both stereoisomers on the LPS-induced TNFa release could almost completely be antagonized by preincubation with the selective beta(2)-AR-antagonist ICI-118551. Further evidence that the effect of the P-agonists is mediated via the beta(2)-adrenoceptor subtype exclusively was acquired by incubation of U937 cells with selective beta(1)- and beta(3)-agonists. None of these receptor subtype agonists showed significant suppressive effect on TNFa release. This study provides additional proof that the anti-inflammatory effects of beta(2)-agonists are mediated via the beta(2)-adrenoceptor and indicates that these effects are highly dependent on the stereoselectivity of the ligand.