Increased synthesis of inflammatory eicosanoids can be primed by innate immune receptor activation.

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 A₂ (PLA₂) enzymes. Pretreatment of MM6 cells with the TLR2 ligands LTA, FSL-1, or Pam₃CSK₄ 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 PLA₂ inhibitors indicated that the increase of AA release is a result of enhanced activity of group IV cPLA₂ in MM6 cells. TLR2 ligands elicited the time-dependent activation of p38 MAPK and ERK1/2 pathways, which led to phosphorylation of cPLA₂α at Ser⁵⁰⁵. Simultaneous inhibition of p38 MAPK and ERK1/2 pathways prevented the increase of cPLA₂α 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 cPLA₂ activation and subsequent LT biosynthesis.