TNF-α Induces Cytosolic Phospholipase A2 Expression in Human Lung Epithelial Cells via JNK1/2- and p38 MAPK-Dependent AP-1 Activation

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Abstract

Background:Cytosolic phospholipase A 2 (cPLA 2 ) plays a pivotal role in mediating agonist-induced arachidonic acid (AA) release for prostaglandin (PG) synthesis during inflammation triggered by tumor necrosis factor-α (TNF-α). However, the mechanisms underlying TNF-α-induced cPLA 2 expression in human lung epithelial cells (HPAEpiCs) were not completely understood.Principal Findings:We demonstrated that TNF-α induced cPLA 2 mRNA and protein expression, promoter activity, and PGE 2 secretion in HPAEpiCs. These responses induced by TNF-α were inhibited by pretreatment with the inhibitor of MEK1/2 (PD98059), p38 MAPK (SB202190), JNK1/2 (SP600125), or AP-1 (Tanshinone IIA) and transfection with siRNA of TNFR1, p42, p38, JNK2, c-Jun, c-Fos, or ATF2. We showed that TNF-α markedly stimulated p42/p44 MAPK, p38 MAPK, and JNK1/2 phosphorylation which were attenuated by their respective inhibitors. In addition, TNF-α also stimulated c-Jun and ATF2 phosphorylation which were inhibited by pretreatment with SP600125 and SB202190, respectively, but not PD98059. Furthermore, TNF-α-induced cPLA 2 promoter activity was abrogated by transfection with the point-mutated AP-1 cPLA 2 construct. Finally, we showed that TNF-α time-dependently induced p300/c-Fos/c-Jun/ATF2 complex formation in HPAEpiCs. On the other hand, TNF-α induced in vivo binding of c-Jun, c-Fos, ATF2, and p300 to the cPLA 2 promoter in these cells. In an in vivo study, we found that TNF-α induced leukocyte count in BAL fluid of mice and cPLA 2 mRNA levels in lung tissues via MAPKs and AP-1.Significance:Taken together, these results demonstrated that TNF-α-induced cPLA 2 expression was mediated through p38 MAPK- and JNK1/2-dependent p300/c-Fos/c-Jun/ATF2 complex formation in HPAEpiCs. © 2013 Lee et al.

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Lee, I. T., Lin, C. C., Cheng, S. E., Hsiao, L. D., Hsiao, Y. C., & Yang, C. M. (2013). TNF-α Induces Cytosolic Phospholipase A2 Expression in Human Lung Epithelial Cells via JNK1/2- and p38 MAPK-Dependent AP-1 Activation. PLoS ONE, 8(9). https://doi.org/10.1371/journal.pone.0072783

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