Laboratório de Farmacologia, Instituto Butantan, Av. Vital Brazil 1500, CEP 05503-900, Sao Paulo, Brazil.
Toxicon. 2011 Feb;57(2):288-96. doi: 10.1016/j.toxicon.2010.12.004. Epub 2010 Dec 10.
In this study, the production of prostaglandin E₂ (PGE₂) and up-regulation in cyclooxygenase (COX) pathway induced by a phospholipase A₂ (PLA₂), myotoxin-III (MT-III), purified from Bothrops asper snake venom, in isolated neutrophils were investigated. The arachidonic acid (AA) production and the participation of intracellular PLA₂s (cytosolic PLA₂ and Ca(2+)-independent PLA₂) in these events were also evaluated. MT-III induced COX-2, but not COX-1 gene and protein expression in neutrophils and increased PGE₂ levels. Pretreatment of neutrophils with COX-2 and COX-1 inhibitors reduced PGE₂ production induced by MT-III. Arachidonyl trifluoromethyl ketone (AACOCF₃), an intracellular PLA₂ inhibitor, but not bromoenol lactone (BEL), an iPLA₂ inhibitor, suppressed the MT-III-induced AA and PGE₂ release. In conclusion, MT-III directly stimulates neutrophils inducing COX-2 mRNA and protein expression followed by production of PGE₂. COX-2 isoform is preeminent over COX-1 for production of PGE₂ stimulated by MT-III. PGE₂ and AA release by MT-III probably is related to cPLA₂ activation.
在这项研究中，研究了从蛇毒中纯化的磷脂酶 A₂（PLA₂）、肌肉毒素-III（MT-III）诱导的前列腺素 E₂（PGE₂）产生和环氧化酶（COX）途径的上调，在分离的嗜中性粒细胞中。还评估了花生四烯酸（AA）的产生以及细胞内 PLA₂（细胞质 PLA₂和 Ca²⁺非依赖性 PLA₂）在这些事件中的参与。MT-III 在嗜中性粒细胞中诱导 COX-2，但不诱导 COX-1 基因和蛋白表达，并增加 PGE₂ 水平。用 COX-2 和 COX-1 抑制剂预处理嗜中性粒细胞可减少 MT-III 诱导的 PGE₂产生。细胞内 PLA₂抑制剂阿魏酰三氟甲基酮（AACOCF₃），但不是 iPLA₂抑制剂溴烯醇内酯（BEL），可抑制 MT-III 诱导的 AA 和 PGE₂释放。总之，MT-III 直接刺激嗜中性粒细胞，诱导 COX-2 mRNA 和蛋白表达，随后产生 PGE₂。与 MT-III 刺激的 COX-1 相比，COX-2 同工型更有利于 PGE₂的产生。MT-III 诱导的 PGE₂ 和 AA 释放可能与 cPLA₂ 的激活有关。
