Secretory phospholipases A(2) isolated from Bothrops asper and from Crotalus durissus terrificus snake venoms induce distinct mechanisms for biosynthesis of prostaglandins E2 and D2 and expression of cyclooxygenases.
The effects of myotoxin III (MT-III), a phospholipase A(2) (sPLA2) from Bothrops asper snake venom, and crotoxin B (CB), a neurotoxic and myotoxic sPLA2 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(2)s promoted the synthesis of PGD2 and PGE2, 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(2)s 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 cPLA2 by AACOCF3, but not of iPLA2 by PACOCF3 or BEL, significantly reduced PGD2, PGE2 and arachidonic acid (AA) release promoted by MT-III. These inhibitors did not affect MT-III-induced COX-2 expression. In contrast, cPLA2 inhibition did not modify the effects of CB, whereas iPLA2 inhibition reduced PGD2 and AA production induced by CB. These findings imply that distinct regulatory mechanisms leading to PGs' synthesis are triggered by these snake venom sPLA(2)s. Such differences are likely to explain the dissimilar patterns of inflammatory reaction elicited by these sPLA(2)s in vivo.
Moreira
Vanessa
V
Laboratório de Farmacologia, Instituto Butantan, São Paulo, Brazil.
Gutiérrez
José Maria
JM
Soares
Andreimar Martins
AM
Zamunér
Stella Regina
SR
Purgatto
Eduardo
E
Teixeira
Catarina de Fátima Pereira
Cde F
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D017837:Bothrops / Q000502:physiology; D002478:Cells, Cultured; D003435:Crotalid Venoms / Q000201:enzymology*; D017839:Crotalus / Q000502:physiology; D003439:Crotoxin / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic; D054501:Group II Phospholipases A2 / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010529:Peritoneal Cavity; D015230:Prostaglandin D2 / Q000096:biosynthesis*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D030162:Reptilian Proteins / Q000494:pharmacology*; D015854:Up-Regulation
D003435:Crotalid Venoms; D030162:Reptilian Proteins; D016718:Arachidonic Acid; D003439:Crotoxin; D011451:Prostaglandin-Endoperoxide Synthases; D054501:Group II Phospholipases A2; C080300:myotoxin III, Bothrops asper; D015232:Dinoprostone; D015230:Prostaglandin D2