The MAP kinase inhibitors, PD098059, UO126 and SB203580, inhibit IL-1 beta-dependent PGE(2) release via mechanistically distinct processes

1 In common with human bronchial epithelial cells, pulmonary A549 cells rel ease prostaglandin (PG) E-2 in response to pro-inflammatory cytokines. We h ave therefore used these cells to examine the effect of the selective mitog en activated protein (MAP) kinase inhibitors; PD098059, a mitogen activated and extracellular regulated kinase kinase (MEK) 1 inhibitor, UO126, a dual MEK1 & MEK2 inhibitor, and SB203580, a p38 MAP kinase inhibitor in the IL- 1 beta-dependent release of PGE(2). 2 Following IL-1 beta treatment the extracellular regulated kinases (ERKs) and the p38 MAP kinases were rapidly phosphorylated. 3 PD09059, UO126 and SB203580 prevented IL-1 beta-induced PGE(2) release at doses that correlated closely with published IC50 values. Small or partial effects at the relevant doses were observed on induction of cyclo-oxygenas e (COX) activity or COX-2 protein suggesting that the primary effects were at the level of arachidonate availability. 4 Neither PD098059 nor SB203580 showed any effect on IL-1 beta-induced arac hidonate release. We therefore speculate that the MEK1/ERK and p38 kinase c ascades play a role in the functional coupling of arachidonate release to C OX-2. 5 In contrast, UO126 was highly effective at inhibiting IL-1 beta-dependent arachidonate release, implicating MEK2 in the activation of the PLA, that is involved in IL-1 beta-dependent PGE2 release. 6 We conclude that the MEK1, MEK2 and p38 MAP kinase inhibitors, PD098059, UO126 and SB203580, are highly potent in respect of inflammatory PG release . Finally, we conclude that these inhibitors act via mechanistically distin ct processes, which may have anti-inflammatory benefits.