Anti-inflammatory effects of dissociated glucocorticoid 21-hidroxi-6,19-epoxyprogesterone are mediated by p38 inactivation

ORQUEDA, A; VELEIRO, AS; BURTON, G.; PECCI, A.

Bariloche

Workshop; SISTAM 2012; 2012

The rigid steroid 21-hidroxi-6,19-epoxyprogesterone (OP) is a selective glucocorticoid receptor (GR) ligand. Our previous results have demonstrated that OP is able to inhibit Ciclooxygenase-2 (Cox-2) and Interleukin-8 (Il-8) gene expression triggered by Tumor Necrosis Factor-alpha (TNF- in A549 lung epithelial cells while it lacks glucocorticoid associated chemoresistance when LM3 tumor epithelial mammary cells are treated with the anti-neoplasic drug paclitaxel. Here we found that OP inhibits in a dose-dependent fashion the Nitric Oxide (NO) formation in RAW 264.7 macrophage cells treated with lipopolysaccharide (LPS). This effect is accompanied by the repression of Nitric Oxide Synthase (Nos-2) expression. Besides, the anti-inflammatory actions of OP would be independent of the NF-B and c-Jun pathways. In order to gain deep knowledge on the molecular mechanism of action of OP, we hypothesized that this steroid may control the p38 Mitogen Activated Protein Kinase (MAPK) pathway. We found that OP diminishes Cox-2 mRNA levels in A549 cells by inhibiting p38 activation triggered by TNF-. Furthermore, this blockade ability disappeared when the dual phosphatase activity was inhibited with sodium orthovanadate (OVNa). Finally, we found increased levels of MKP-1 protein in A549 cells treated with OP. Together, our results suggest that OP exerts their anti-inflammatory actions trough the inactivation of the p38 pathway.