Role of Ca(2+)-independent phospholipase A(2) and cyclooxygenase/lipoxygenase pathways in the nitric oxide production by murine macrophages stimulated by lipopolysaccharides.
There is evidence of molecular cross talk between inflammatory mediators such as nitric oxide (NO) and prostaglandins (PG), which may regulate tissue homeostasis and contribute to pathophysiological processes. Here we examine the role of endogenous arachidonic acid (AA) and its AA metabolites in the regulation of NO release by lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7. Our results suggest that bromoenol lactone-sensitive phospholipase A(2) is involved in AA release and the subsequent PG and leukotriene (LT) production. The cyclooxygenase inhibitor, indomethacin, and lipoxygenase inhibitors such as baicalein and zileuton blocked the dose-dependent PGE(2) or LTB(4) and nitrite (NO(2)(-)) production induced by LPS. Furthermore, the effects of indomethacin were reverted by exogenous PGE(2) and forskolin, whereas AH23848B, an EP(4) PGE(2) subtype receptor antagonist, decreased NO(2)(-) release. On the other hand, the effect of baicalein on NO(-)(2) production was reverted by exogenous LTB(4) and the fibrate WY 14,643, a natural and a synthetic peroxisome proliferator-activated receptor alpha (PPAR alpha), respectively. Thus, PGE(2) via EP(4) receptor/cAMP and LTB(4) via PPAR alpha may be involved in the control of NO synthesis by LPS in macrophage RAW 264.7 cultures.
Vivancos
Marta
M
Departamento de Fisiología, Facultad de Farmacia, Universidad de Barcelona, Avda. Joan XXIII s/n, E-08028 Barcelona, Spain.
Moreno
Juan J
JJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D015232:Dinoprostone / Q000096:biosynthesis; D007975:Leukotriene B4 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008084:Lipoxygenase / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010741:Phospholipases A / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D008070:Lipopolysaccharides; D007975:Leukotriene B4; D016718:Arachidonic Acid; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D015232:Dinoprostone; D002118:Calcium