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

Author(s)

Moreira, Vanessa ^[1] ; Maggio de Castro Souto, Pollyana Cristina ^[1] ; Ramirez Vinolo, Marco Aurelio ^[2] ; Lomonte, Bruno ^[3] ; Gutierrez, Jose Maria ^[3] ; Curi, Rui ^[2] ; Teixeira, Catarina ^[1]

Affiliation

^[1] Inst Butantan, Farmacol Lab, BR-05503900 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Fisiol, BR-05508 Sao Paulo - Brazil

^[3] Univ Costa Rica, Fac Microbiol, Inst Clodomiro Picado, San Jose - Costa Rica

• Document type: Journal article
• Source: European Journal of Pharmacology; v. 708, n. 1-3, p. 68-79, MAY 15 2013.
• Web of Science Citations: 6

Abstract

The effects of a snake venom Lys-49 phospholipase A(2) (PLA(2)) homolog 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 Ca2+ 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 kappa B (NF-kappa 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-kappa 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-kappa 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) homolog 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-kappa B, cPLA(2) and distinct protein kinases are the principal steps involved in these cellular events. (C) 2013 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 08/57898-0 - National Institute of Science and Technology on Toxins
• Grantee: Osvaldo Augusto Brazil Esteves Sant'Anna
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/07630-1 - Signaling pathways activated by GPR43 and their involvement in neutrophils migration in vitro and in experimental model of periodontal disease
• Grantee: Marco Aurélio Ramirez Vinolo
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 07/03337-5 - Effects of two phospholipases A2, isolated from snake venom on NF-kappaB activation pathways related to COX-2 and mPGE synthase-1 expression: involvement of macrophage mannose receptors
• Grantee: Vanessa Moreira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral