Mechanisms of prostaglandin E2-induced interleukin-6 release in astrocytes: possible involvement of EP4-like receptors, p38 mitogen-activated proteinkinase and protein kinase C

The expression of cyclooxygenase-2 (COX-2) and the synthesis of prostagland in E2 (PGE(2)) as well as of cytokines such as interleukin-6 (IL-6) have al l been suggested to propagate neuropathology in different brain disorders s uch as HIV-dementia, prion diseases, stroke and Alzheimer's disease. In thi s report, we show that PGE(2)-stimulated IL-6 release in U373 MG human astr oglioma cells and primary rat astrocytes. PGE(2)-induced intracellular cAMP formation was mediated via prostaglandin E receptor 2 (EP2), but inhibitio n of cAMP formation and protein kinase A or blockade of EP1/EP2 receptors d id not affect PGE(2)-induced IL-6 synthesis. This indicates that the cAMP p athway is not part of PGE(2)-induced signal transduction cascade leading to IL-6 release. The EP3/EP1-receptor agonist sulprostone failed to induce IL -6 release, suggesting an involvement of EP4-like receptors. PGE(2)-activat ed p38 mitogen-activated kinase (p38 MAPK) and protein kinase C (PKC). PGE( 2)-induced IL-6 synthesis was inhibited by specific inhibitors of p38 MAPK (SB202190) and PKC (GF203190X). Although, up to now, EP receptors have only rarely been linked to p38 MAPK or PKC activation, these results suggest th at PGE(2) induces IL-6 via an EP4-like receptor by the activation of PKC an d p38 MAPK via an EP4-like receptor independently of cAMP.