TLR2 ligands augment cPLA2α 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.

TLR4‐dependent induction of vascular adhesion molecule‐1 in rheumatoid arthritis synovial fibroblasts: Roles of cytosolic phospholipase A2α/cyclooxygenase‐2

“…The activation of cPLA 2 a requires phosphorylation at multiple sites which can be regulated by p38 MAPK and ERK1/2 activation. Previous studies have indicated that ERK1/2 or p38 MAPK phosphorylates cPLA 2 a at Ser 505 and then promotes cPLA 2 a activity in several cell types (Qi and Shelhamer, 2005;Kikawada et al, 2007;Pavicevic et al, 2008;Lindner et al, 2009). Our data provide evidence that LPS triggered cPLA 2 a phosphorylation at Ser 505 through an ERK-dependent pathway, but not p38 MAPK (Figs.…”

Leishmania donovani-Induced Prostaglandin E2 Generation Is Critically Dependent on Host Toll-Like Receptor 2–Cytosolic Phospholipase A2 Signaling

“…Previously, the extracellular pattern recognition receptor TLR2 has been reported to activate cPLA2 (26). Moreover, the Leishmania surface molecule lipophosphoglycan (LPG) can interact with the macrophage-expressed TLR2 to modulate macrophage effector functions (27).…”

Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression

“…Indeed, TLR ligands have been shown to promote LT biosynthesis (37,38). Furthermore, both LTB 4 (39) and CysLTs (40) have themselves been reported to activate NF-κB in specific cells and contexts.…”