Activation of mitogen-activated protein kinase by fumonisin B-1 stimulatescPLA(2) phosphorylation, the arachidonic acid cascade and cAMP production

Activation of mitogen-activated protein kinase (MAPK) results in pleiotropi c effects such as modulation of the transcription and activation of enzymes involved in signal transduction. One such enzyme is the cytoplasmic phosph olipase A(2) (cPLA(2)), which releases arachidonic acid (AA), AA is the pre cursor of prostaglandins and leukotrienes, two inflammatory mediators, whic h regulate gene expression and protein kinase (PK) activity. Fumonisin B-1 (FB1) was shown to increase PKC translocation and stimulate MAPK, We have i nvestigated the effect of FB1 on the AA cascade in a human epithelial cell line and the signal transduction pathway regulating PLA(2) activation, We o bserved that FB1 stimulated cPLA(2) activity and increased AA release by a mechanism independent of PKC activation and that the activation of cPLA(2) is a two-step process: the First is phosphorylation of cPLA(2) by MAPK; the second is a consequence of the increase in sphingosine inside and outside the cells after 2 h, which is known to induce a rise in intracellular free calcium. Overall, this suggests that the effect of FB1 on cells is partiall y dependent on the action of FB1 on the enzymes involved in the cell cycle, such as MAPK and PKA, and on bioactive fatty acids, such as the prostaglan dins and leukotrienes, and also on disruption of sphingolipid metabolism. I n addition, we have observed down-regulation of cPLA(2) activity and AA met abolism by a mechanism involving prostaglandin production, cAMP synthesis a nd PKA activation.