Inhibition of NF kappa B-mediated pro-inflammatory gene expression in rat mesangial cells by the enolized 1,3-dioxane-4,6-dione-5-carboxamide, CGP-43182

1 CGP-43182 has been described as a potent inhibitor of group IIA secreted phospholipase A(2) (group HA sPLA(2)) activity in vitro. In rat mesangial c ells, inhibition of group IIA sPLA(2) activity by CGP-43182 results in a 70 % reduction of cytokine-stimulated prostaglandin E-2 biosynthesis, suggesti ng that group IIA sPLA(2) participates in arachidonic acid release and eico sanoid formation. Under these conditions the cytosolic phospholipase A(2) i s not affected. 2 In mesangial cells, in addition to inhibition of catalytic activity, the membrane-permeant CGP-43182 completely blocked interleukin 1 beta (IL1 beta )-stimulated group IIA sPLA(2) gene expression. 3 A further action of CGP-43182 was a complete inhibition of cyclo-oxygenas e-2 gene expression, resulting in a drastic reduction of prostaglandin form ation in mesangial cells. 4 Moreover, CGP-43182 completely blocked IL1 beta-induced gene expression o f the inducible nitric oxide synthase, leading to an inhibition of cytokine -stimulated nitric oxide formation. 5 In contrast, the stimulatory effect of the cell-permeant cyclic AMP-analo gue, dibutyryl-cAMP, on the induction of these enzymes was not inhibited by CGP-43182. These data indicate that CGP-43182 interferes with IL1 beta- bu t not cyclic AMP-activated transcriptional regulation. 6 By studying components of the upstream transcription machinery, we observ ed an inhibition of NF kappa B activation by CGP-43182 in IL1 beta-treated cells. Moreover, we observed that CGP-43182 prevented the phosphorylation a nd proteolytic degradation of the endogenous NF kappa B inhibitor, I kappa B, a process necessary for NF kappa B activation. 7 From our data, we propose that CGP-43182 is a potent anti-inflammatory dr ug useful for preventing the consequences of a concerted action of cytokine -stimulated pro-inflammatory genes mediated by NF kappa B.