Investigation into the involvement of phospholipases A2 and MAP kinases in modulation of AA release and cell growth in A549 cells

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Abstract
We have investigated the contribution of specific PLA2s to eicosanoid release from A549 cells by using specific inhibitors of secretory PLA2 (ONO‐RS‐82 and oleyloxyethylphosphocholine), cytosolic PLA2 (AACOCF3 and MAFP) and calcium‐independent PLA2 (HELSS, MAFP and PACOCF3). Similarly, by using specific inhibitors of p38 MAPK (SB 203580), ERK1/2 MAPK (Apigenin) and MEK1/2 (PD 98059) we have further evaluated potential pathways of AA release in this cell line. ONO‐RS‐82 and oleyloxyethylphosphocholine had no significant effect on EGF or IL‐1β stimulated 3H‐AA or PGE2 release or cell proliferation. AACOCF3, HELSS, MAFP and PACOCF3 significantly inhibited both EGF and IL‐1β stimulated 3H‐AA and PGE2 release as well as cell proliferation. Apigenin and PD 98509 significantly inhibited both EGF and IL‐1β stimulated 3H‐AA and PGE2 release and cell proliferation whereas, SB 203580 had no significant effect on EGF or IL‐1β stimulated 3H‐AA release, or cell proliferation but significantly suppressed EGF or IL‐1β stimulated PGE2 release. These results confirm that the liberation of AA release, generation of PGE2 and cell proliferation is mediated largely through the actions of cPLA2 whereas, sPLA2 plays no significant role. We now also report a hitherto unsuspected contribution of iPLA2 to this process and demonstrate that the stimulating action of EGF and IL‐1β in AA release and cell proliferation is mediated in part via a MEK and ERK‐dependent pathway (but not through p38MAPK). We therefore propose that selective inhibitors of MEK and MAPK pathways may be useful in controlling AA release, eicosanoid production and cell proliferation. British Journal of Pharmacology (2000) 131, 255–265; doi:10.1038/sj.bjp.0703573

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