A Nuclear Receptor Ligand Down-Regulates Cytosolic Phospholipase A2 Expression to Reduce Bile Acid?Induced Cyclooxygenase 2 Activity in Cholangiocytes: Implications of Anticarcinogenic Action of Farnesoid X Receptor Agonists

2005 ◽  
Vol 50 (3) ◽  
pp. 514-524 ◽  
Author(s):  
Daisuke Komichi ◽  
Susumu Tazuma ◽  
Tomoji Nishioka ◽  
Hideyuki Hyogo ◽  
Kazuaki Chayama
Keyword(s):  
Bile Acid ◽  
Phospholipase A2 ◽  
Nuclear Receptor ◽  
Cytosolic Phospholipase A2 ◽  
Cyclooxygenase 2 ◽  
Farnesoid X Receptor ◽  
Receptor Ligand ◽  
Receptor Agonists ◽  
Cytosolic Phospholipase

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

2016 ◽  
Vol 84 (10) ◽  
pp. 2963-2973 ◽  
Author(s):  
Amrita Bhattacharjee ◽  
Saikat Majumder ◽  
Shibali Das ◽  
Sweta Ghosh ◽  
Satabdi Biswas ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Phospholipase A2 ◽  
Leishmania Donovani ◽  
Cytosolic Phospholipase A2 ◽  
Cyclooxygenase 2 ◽  
Toll Like Receptor ◽  
Content Type ◽  
Cytosolic Phospholipase ◽  
Pge2 Release ◽  
Toll Like Receptor 2

Visceral leishmaniasis (VL) is the second-largest parasitic killer disease after malaria. During VL, the protozoanLeishmania donovaniinduces prostaglandin E2 (PGE2) generation within host macrophages to aid parasite survival. PGE2 significantly influences leishmanial pathogenesis, asL. donovaniproliferation is known to be attenuated in PGE2-inhibited macrophages. Here, we report for the first time that signaling via macrophage Toll-like receptor 2 (TLR2) plays an instrumental role in inducing PGE2 release fromL. donovani-infected macrophages. This signaling cascade, mediated via the TLR2–phosphatidylinositol 3-kinase (PI3K)–phospholipase C (PLC) signaling pathway, was found to be indispensable for activation of two major enzymes required for PGE2 generation: cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (Cox2). Inhibition of cPLA2, but not secreted phospholipase A2 (sPLA2) or calcium-independent phospholipase A2 (iPLA2), arrestedL. donovaniinfection. During infection, cPLA2 activity increased >7-fold in a calcium-dependent and extracellular signal-regulated kinase (ERK)-dependent manner, indicating that elevation of intracellular calcium and ERK-mediated phosphorylation was necessary forL. donovani-induced cPLA2 activation. For transcriptional upregulation of cyclooxygenase 2, activation of the calcium-calcineurin-nuclear factor of activated T cells (NFAT) signaling was required in addition to the TLR2-PI3K-PLC pathway. Detailed studies by site-directed mutagenesis of potential NFAT binding sites and chromatin immunoprecipitation (ChIP) analysis revealed that the binding of macrophage NFATc2, at the −73/−77 site on thecox2promoter, inducedL. donovani-drivencox2transcriptional activation. Collectively, these findings highlight the contribution of TLR2 downstream signaling toward activation of cPLA2 and Cox2 and illustrate how the TLR2-PI3K-PLC pathway acts in a concerted manner with calcium-calcineurin-NFATc2 signaling to modulate PGE2 release fromL. donovani-infected macrophages.

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