title: Stereoselectivity at the beta2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of beta2-agonists.
abstract: Previous research has shown that beta-adrenoceptor (beta-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 TNFalpha 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 beta2-AR agonist TA2005 [(R,R)- and (S,S)-] on the LPS-induced TNFalpha and IL-10 release by U937 macrophages was compared. The (R,R)-stereoisomer was 277 times more potent in inhibiting the TNFalpha release than the (S,S)-form. The (R,R)-stereoisomer also appeared to be more potent in increasing the IL-10 release. In radioligand binding studies the affinity of (R,R)-TA2005 for the beta-adrenoceptor was 755 times higher than the (S,S)-TA2005 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 TNFalpha release could almost completely be antagonized by preincubation with the selective beta2-AR-antagonist ICI-118551. Further evidence that the effect of the beta-agonists is mediated via the beta2-adrenoceptor subtype exclusively was acquired by incubation of U937 cells with selective beta1- and beta3-agonists. None of these receptor subtype agonists showed significant suppressive effect on TNFalpha release. This study provides additional proof that the anti-inflammatory effects of beta2-agonists are mediated via the beta2-adrenoceptor and indicates that these effects are highly dependent on the stereoselectivity of the ligand.
authors.affiliation: Department of Pharmacology, TNO Pharma, AJ Zeist, The Netherlands. izeboud@voeding.tno.nl
authors.forename: C A
authors.initials: CA
authors.lastname: Izeboud
authors.forename: R M
authors.initials: RM
authors.lastname: Vermeulen
authors.forename: A
authors.initials: A
authors.lastname: Zwart
authors.forename: H P
authors.initials: HP
authors.lastname: Voss
authors.forename: A S
authors.initials: AS
authors.lastname: van Miert
authors.forename: R F
authors.initials: RF
authors.lastname: Witkamp
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects*; D011869:Radioligand Assay; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D015398:Signal Transduction; D013237:Stereoisomerism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000242:Cyclic AMP