12-HETE is a regulator of PGE(2) production via COX-2 expression induced by a snake venom group IIA phospholipase A(2) in isolated peritoneal macrophages

Author(s)

Moreira, Vanessa ^[1] ; Gutierrez, Jose Maria ^[2] ; Lomonte, Bruno ^[2] ; Ramirez Vinolo, Marco Aurelio ^[3] ; Curi, Rui ^[4] ; Lambeau, Gerard ^[5] ; Teixeira, Catarina ^[6]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Farmacol, Sao Paulo, SP - Brazil

^[2] Univ Costa Rica, Fac Microbiol, Inst Clodomiro Picado, San Jose - Costa Rica

^[3] Univ Estadual Campinas, Inst Biol, Dept Genet Evolucao & Bioagentes, Campinas, SP - Brazil

^[4] Univ Sao Paulo, Inst Ciencias Biomed, Dept Fisiol, Sao Paulo - Brazil

^[5] Univ Ate dAzur, CNRS, IPMC, Valbonne Sophia Antipoli - France

^[6] Inst Butantan, Lab Farmacol, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Chemico-Biological Interactions; v. 317, FEB 1 2020.
• Web of Science Citations: 1

Abstract

The snake venom miotoxin (MT)-III is a group IIA secreted phospholipase A(2) (sPLA(2)) with pro-inflammatory activities. Previous studies have demonstrated that MT-III has the ability to stimulate macrophages to release inflammatory lipid mediators derived from arachidonic acid metabolism. Among them, we highlight prostaglandin (PG)E-2 produced by the cyclooxygenase (COX)-2 pathway, through activation of nuclear factor (NF)-kappa B. However, the mechanisms coordinating this process are not fully understood. This study investigates the regulatory mechanisms exerted by other groups of bioactive eicosanoids derived from 12-lipoxygenase (12-LO), in particular 12-hydroxyeicosatetraenoic (12-HETE), on group IIA sPLA(2)-induced (i) PGE(2) release, (ii) COX-2 expression, and (iii) activation of signaling pathways p38 mitogen-activated protein kinases(p38MAPK), protein C kinase (PKC), extracellular signal-regulated kinase 1/2 (ERK1/2), and NF-kappa B. Stimulation of macrophages with group IIA sPLA(2) resulted in release of 12-HETE without modification of 12-LO protein levels. Pre-treatment of these cells with baicalein, a 12-LO inhibitor, decreased the sPLA(2)-induced PGE(2) production, significantly reduced COX-2 expression, and inhibited sPLA2-induced ERK; however, it did not affect p38MAPK or PKC phosphorylation. In turn, sPLA(2)-induced PGE(2) release and COX-2 expression, but not NF-kappa B activation, was attenuated by pre-treating macrophages with PD98059 an inhibitor of ERK1/2. These results suggest that, in macrophages, group IIA sPLA(2)-induced PGE(2) release and COX-2 protein expression are distinctly mediated through 12-HETE followed by ERK1/2 pathway activation, independently of NF-kappa B activation. These findings highlight an as yet undescribed mechanism by which 12-HETE regulates one of the distinct signaling pathways for snake venom group IIA sPLA(2)-induced PGE(2) release and COX-2 expression in macrophages. (AU)

• FAPESP's process: 12/10653-9 - Role of short chain fatty acids and their receptor (GPR43) in the immune response to anaerobic bacteria in vivo and in vitro
• Grantee: Marco Aurélio Ramirez Vinolo
• Support Opportunities: Research Grants - Young Investigators Grants
• 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