The aim of the present study is to explore the signaling pathway associated with Naja naja atra phospholipase A(2) (PLA(2))-induced apoptotic death of human leukemia U937 cells. Degradation of procaspases, production of tBid, loss of mitochondrial membrane potential, and cytochrome c release were observed in PLA(2)-treated cells. PLA(2) treatment increased Fas and FasL protein expression, and upregulated transcription of Fas and FasL mRNA. Upon exposure to PLA(2), ROS generation, p38 MAPK activation, and ERK inactivation were found in U937 cells. Abolition of PLA(2)-induced ROS generation abrogated p38 MAPK activation and upregulation of Fas and FasL expression, but restored ERK activation and viability of PLA(2)-treated cells. Block of p38 MAPK by SB202190 abolished PLA(2)-induced Fas/FasL upregulation and ERK inactivation, but not ROS generation. Activated ERK suppressed p38 MAPK activation and Fas/FasL protein expression. Selective inactivation or overexpression of p38alpha MAPK proved that upregulation of Fas/FasL and ERK inactivation were related to p38alpha MAPK activation. Deprivation of catalytic activity with PLA(2) blocked completely PLA(2)-induced Fas/FasL upregulation. Downregulation of FADD abolished PLA(2)-induced procaspase-8 degradation and rescued viability of PLA(2)-treated cells. Taken together, our results indicate that Fas/FasL upregulation in PLA(2)-treated U937 cells is elicited by ROS-mediated p38alpha MAPK activation and ERK inactivation, and suggest that autocrine Fas/FasL apoptotic mechanism is involved in PLA(2)-induced cell death. J. Cell. Physiol. 219: 642-651, 2009. (c) 2009 Wiley-Liss, Inc.

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