title: An Asp49 phospholipase A2 from snake venom induces cyclooxygenase-2 expression and prostaglandin E2 production via activation of NF-κB, p38MAPK, and PKC in macrophages.
abstract: Phospholipases A2 (PLA2) are key enzymes for production of lipid mediators. We previously demonstrated that a snake venom sPLA2 named MT-III leads to prostaglandin (PG)E2 biosynthesis in macrophages by inducing the expression of cyclooxygenase-2 (COX-2). Herein, we explored the molecular mechanisms and signaling pathways leading to these MT-III-induced effects. Results demonstrated that MT-III induced activation of the transcription factor NF-κB in isolated macrophages. By using NF-κB selective inhibitors, the involvement of this factor in MT-III-induced COX-2 expression and PGE2 production was demonstrated. Moreover, MT-III-induced COX-2 protein expression and PGE2 release were attenuated by pretreatment of macrophages with SB202190, and Ly294002, and H-7-dihydro compounds, indicating the involvement of p38MAPK, PI3K, and PKC pathways, respectively. Consistent with this, MT-III triggered early phosphorylation of p38MAPK, PI3K, and PKC. Furthermore, SB202190, H-7-dihydro, but not Ly294002 treatment, abrogated activation of NF-κB induced by MT-III. Altogether, these results show for the first time that the induction of COX-2 protein expression and PGE2 release, which occur via NF-κB activation induced by the sPLA2-MT-III in macrophages, are modulated by p38MAPK and PKC, but not by PI3K signaling proteins.
authors.affiliation: Laboratório de Farmacologia, Instituto Butantan, Avenida Vital Brazil 1500, 05503-900 São Paulo, SP, Brazil.
authors.forename: Vanessa
authors.identifier: 0000-0002-4048-1967
authors.initials: V
authors.lastname: Moreira
authors.affiliation: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lomonte
authors.affiliation: Departamento de Genética, Evolução e Bioagentes, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, SP, Brazil.
authors.forename: Marco Aurélio Ramirez
authors.initials: MA
authors.lastname: Vinolo
authors.affiliation: Departamento de Fisiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.affiliation: Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
authors.forename: José María
authors.initials: JM
authors.lastname: Gutiérrez
authors.affiliation: Laboratório de Farmacologia, Instituto Butantan, Avenida Vital Brazil 1500, 05503-900 São Paulo, SP, Brazil.
authors.forename: Catarina
authors.initials: C
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2 / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012910:Snake Venoms / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002867:Chromones; D007093:Imidazoles; D009025:Morpholines; D016328:NF-kappa B; D011725:Pyridines; D012910:Snake Venoms; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D054467:Phospholipases A2; D015232:Dinoprostone; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole