title: TLR2 ligands augment cPLA2alpha activity and lead to enhanced leukotriene release in human monocytes.
abstract: Toll-like receptors (TLRs) play an important role in innate immunity. They detect pathogen-associated receptor patterns (PAMPs) and initiate subsequent immune responses. Present studies investigate the influence of TLR2 ligands on leukotrienes (LT) formation in human monocytes. LTs are proinflammatory mediators derived from arachidonic acid (AA), which is released from membranes by phospholipase A(2) (PLA(2)) enzymes. Pretreatment of MM6 cells with the TLR2 ligands LTA, FSL-1, or Pam(3)CSK(4) resulted in an up to two- to threefold enhancement of ionophore-induced LT formation in a dose- and time-dependent manner and to an augmentation of ionophore-induced AA release with similar kinetics. Also in human peripheral blood mononuclear cells (hPBMC), TLR2 activators increased LT formation. Studies with PLA(2) inhibitors indicated that the increase of AA release is a result of enhanced activity of group IV cPLA(2) in MM6 cells. TLR2 ligands elicited the time-dependent activation of p38 MAPK and ERK1/2 pathways, which led to phosphorylation of cPLA(2)alpha at Ser(505). Simultaneous inhibition of p38 MAPK and ERK1/2 pathways prevented the increase of cPLA(2)alpha phosphorylation and the augmentation of AA release. TLR2 ligand-induced increase of AA release was blocked by a neutralizing anti-hTLR2 antibody, indicating that TLR2 mediates augmented cPLA(2) activation and subsequent LT biosynthesis.
authors.affiliation: Institute of Pharmaceutical Chemistry/Center for Drug Research, Development, and Safety (ZAFES), Goethe University, Frankfurt/Main, Germany.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Lindner
authors.forename: Ulrike
authors.initials: U
authors.lastname: Köhl
authors.forename: Thorsten J
authors.initials: TJ
authors.lastname: Maier
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Bernd L
authors.initials: BL
authors.lastname: Sorg
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D016718:Arachidonic Acid / Q000096:biosynthesis; D002460:Cell Line; D004075:Diglycerides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology; D018836:Inflammation Mediators / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism*; D055666:Lipopeptides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D004075:Diglycerides; D004791:Enzyme Inhibitors; C460864:FSL-1 lipoprotein, synthetic; D018836:Inflammation Mediators; D015289:Leukotrienes; D055666:Lipopeptides; D009842:Oligopeptides; C508075:Pam(3)CSK(4) peptide; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D016718:Arachidonic Acid; D054513:Group IV Phospholipases A2