A catalytically-inactive snake venom Lys49 phospholipase A(2) homologue induces expression of cyclooxygenase-2 and production of prostaglandins through selected signaling pathways in macrophages.

A catalytically-inactive snake venom Lys49 phospholipase A(2) homologue induces expression of cyclooxygenase-2 and production of prostaglandins through selected signaling pathways in macrophages.

Eur J Pharmacol. 2013 Feb 14;

Authors: Moreira V, de Castro Souto PC, Ramirez Vinolo MA, Lomonte B, Mar�a Guti�rrez J, Curi R, Teixeira C

Abstract
The effects of a snake venom Lys-49 phospholipase A(2) (PLA(2)) homologue named MT-II, devoid of enzymatic activity, on the biosynthesis of prostaglandins and protein expression of cyclooxygenase-2 (COX-2) and signaling pathways involved were evaluated in mouse macrophages in culture and in peritoneal cells ex vivo. Stimulation of macrophages with MT-II leads to production of prostaglandin D(2) (PGD(2)) and prostaglandin E(2) (PGE(2)) and protein expression of COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1). Inhibition of cytosolic PLA(2) (cPLA(2)), but not Ca(+2) independent PLA(2) (iPLA(2)) reduced release of PGD(2) and PGE(2) and expression of COX-2 induced by MT-II. Inhibition of nuclear factor ?B (NF-?B) significantly reduced MT-II-induced PGE(2), but not PGD(2) production and COX-2 expression. Inhibitors of either protein kinase C (PKC), protein tyrosine kinase (PTK), or extracellular signal-regulated kinase (ERK) pathways abrogated MT-II-induced NF-?B activation and reduced COX-2 expression and PGE(2) release, whereas the p38 mitogen-activated protein kinase (MAPK) inhibitor reduced MT-II-induced COX-2 expression and PGD(2) production. Inhibition of phosphatidylinositol-3-kinase (PI3K) pathway abrogated MT-II-induced NF-?B activation, but affected neither prostaglandins production nor COX-2 expression. MT-II-induced production of PGD(2) and PGE(2) and COX-2 expression were also observed in vivo after intraperitoneal injection into mice. Collectively, our data demonstrate that a catalytically-inactive PLA(2) homologue is capable of inducing prostaglandins biosynthesis and COX-2 expression in macrophages in both in vitro and in vivo models, indicating that the enzymatic activity of PLA(2) is not necessary to trigger these effects. MT-II-activated NF-?B, cPLA(2) and distinct protein kinases are the principal steps involved in these cellular events.

PMID: 23416211 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors