Secretory phospholipases A 2 isolated from Bothrops asper and from Crotalus durissus terrificus snake venoms induce distinct mechanisms for biosynthesis of prostaglandins E 2 and D 2 and expression of cyclooxygenases

Abstract

The effects of myotoxin III (MT-III), a phospholipase A 2 (sPLA 2) from Bothrops asper snake venom, and crotoxin B (CB), a neurotoxic and myotoxic sPLA 2 from the venom of Crotalus durissus terrificus, on cyclooxygenases (COXs) expression and biosynthesis of prostaglandins (PGs) were evaluated, together with the mechanisms involved in these effects. Upon intraperitoneal injection in mice, both sPLA 2s promoted the synthesis of PGD 2 and PGE 2, with a different time-course. MT-III, but not CB, induced COX-2 expression by peritoneal leukocytes without modification on COX-1 constitutive expression, whereas CB increased the constitutive activity of COX-1. MT-III increased the enzymatic activity of COX-1 and COX-2. Similar effects were observed when these sPLA 2s were incubated with isolated macrophages, evidencing a direct effect on these inflammatory cells. Moreover, both toxins elicited the release of arachidonic acid from macrophages in vitro. Inhibition of cPLA 2 by AACOCF 3, but not of iPLA 2 by PACOCF 3 or BEL, significantly reduced PGD 2, PGE 2 and arachidonic acid (AA) release promoted by MT-III. These inhibitors did not affect MT-III-induced COX-2 expression. In contrast, cPLA 2 inhibition did not modify the effects of CB, whereas iPLA 2 inhibition reduced PGD 2 and AA production induced by CB. These findings imply that distinct regulatory mechanisms leading to PGs' synthesis are triggered by these snake venom sPLA 2s. Such differences are likely to explain the dissimilar patterns of inflammatory reaction elicited by these sPLA 2s in vivo.