Abstract
Cytosolic phospholipase A2 (cPLA2) plays a pivotal role in mediating agonist-induced arachidonic acid (AA) release for prostaglandin (PG) synthesis during inflammation triggered by tumor necrosis factor-a (TNF-a). However, the mechanisms underlying TNF-a-induced cPLA2 expression in human lung epithelial cells (HPAEpiCs) were not completely understood. Here, we demonstrated that TNF-a induced cPLA2 mRNA and protein expression, promoter activity, and PGE2 secretion in HPAEpiCs. TNF-a-inducedresponses were inhibited by the inhibitor of Jak2 (AG490), PDGFR (AG1296), PI3K (LY294002), or MEK1/2 (PD98059) and transfection with siRNA of Jak2, PDGFR, Akt, or p42. TNF-a also stimulated Jak2, PDGFR, Akt, and p42/p44 MAPK phosphorylation, which were attenuated by their respective inhibitors. TNF-a stimulated Akt activation via a Jak2/PDGFR pathway. In addition, TNF-a-induced p42/p44 MAPK phosphorylation was reduced by AG1296 or LY294002. Moreover, TNF-a could induce Akt and p42/p44 MAPK translocation from the cytosol into the nucleus, which was inhibited by AG490, AG1296, or LY294002. Finally, TNF-a-stimulated Elk-1 phosphorylation was reduced by LY294002 or PD98059. We also observed that TNF-a time-dependently induced p300/Elk-1 and p300/Akt complex formation, which was reduced by AG490, AG1296, or LY294002. The activity of cPLA2 protein up-regulated by TNF-a was reflected on the PGE2 release which was reduced by AG490, AG1296, LY294002, or PD98059.These results demonstrated that TNF-a-induced cPLA2 expression and PGE2 release was mediated through a Jak2/PDGFR/PI3K/Akt/p42/p44 MAPK/Elk-1 pathway in HPAEpiCs.
- © 2014 ERS