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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 A 2 ‐treated U937 cells
Author(s) -
Liu WenHsin,
Cheng YunChing,
Chang LongSen
Publication year - 2009
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21713
Subject(s) - fas ligand , mapk/erk pathway , downregulation and upregulation , microbiology and biotechnology , p38 mitogen activated protein kinases , autocrine signalling , viability assay , apoptosis , biology , chemistry , programmed cell death , signal transduction , cell culture , biochemistry , genetics , gene
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.