Agradecimentos: Vicerrectoria de Investigacion (Universidad de Costa Rica)

Phospholipases A(2) (PLA(2)) are key enzymes for production of lipid mediators. We previously demonstrated that a snake venom sPLA(2) named MT-III leads to prostaglandin (PG)E-2 biosynthesis in macrophages by inducing the expression of cyclooxygenase-2 (COX-2). Herein, we explored the molecular...

Phospholipases A(2) (PLA(2)) are key enzymes for production of lipid mediators. We previously demonstrated that a snake venom sPLA(2) named MT-III leads to prostaglandin (PG)E-2 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-kappa B in isolated macrophages. By using NF-kappa B selective inhibitors, the involvement of this factor in MT-III-induced COX-2 expression and PGE(2) production was demonstrated. Moreover, MT-III-induced COX-2 protein expression and PGE(2) 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-kappa B induced by MT-III. Altogether, these results show for the first time that the induction of COX-2 protein expression and PGE(2) release, which occur via NF-kappa B activation induced by the sPLA(2)-MT-III in macrophages, are modulated by p38MAPK and PKC, but not by PI3K signaling proteins

FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP

02/13863-2; 07/03336-9; 07/03337-5; 12/10653-9

CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ

306099/2008-0

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