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ROS-mediated p38α MAPK activation and ERK inactivation responsible for upregulation of Fas and FasL and autocrine Fas-mediated cell death in Taiwan cobra phospholipase A2-treated U937 cells

✍ Scribed by Wen-Hsin Liu; Yun-Ching Cheng; Long-Sen Chang

Publisher
John Wiley and Sons
Year
2009
Tongue
English
Weight
442 KB
Volume
219
Category
Article
ISSN
0021-9541

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✦ Synopsis

Abstract

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 p38α MAPK proved that upregulation of Fas/FasL and ERK inactivation were related to p38α 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 p38α 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. © 2009 Wiley‐Liss, Inc.

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