VASOACTIVE-INTESTINAL-PEPTIDE AND FORSKOLIN STIMULATE INTERLEUKIN-6 PRODUCTION BY RAT CORTICAL ASTROCYTES IN CULTURE VIA A CYCLIC-AMP-DEPENDENT, PROSTAGLANDIN-INDEPENDENT MECHANISM

In this study we analyzed the involvement of the cyclic AMP (cAMP)-pro tein kinase A system in the regulation of interleukin 6 production by cultured cortical astrocytes. Vasoactive intestinal peptide strongly i ncreased, in a dose-dependent manner, interleukin 6 production. This e ffect was reduced when protein kinase A was blocked by KT-5720; it was not affected by calphostin C, a protein kinase C inhibitor. Forskolin caused a concentration-dependent increase in interleukin 6 release th at was also inhibited by KT-5720. Because prostaglandins are believed to play a role in interleukin 6 production, we tried to determine whet her the stimulatory effects of vasoactive intestinal peptide and forsk olin on cytokine release might be mediated by stimulation of prostagla ndin production in cortical astrocytes. Vasoactive intestinal peptide did not increase the production of either prostaglandin E(2) or F-2 al pha. Conversely, forskolin concentration-dependently stimulated the pr oduction of both prostaglandins, an effect that was blocked by indomet hacin. Indomethacin did not affect either vasoactive intestinal peptid e- or forskolin-stimulated interleukin 6 production. To exclude the po ssibility that prostaglandins participate in interleukin 6 production induced by forskolin, we tested prostaglandins E(2) and F-2 alpha. The former was completely ineffective in eliciting the cytokine productio n, whereas prostaglandin F-2 alpha slightly increased interleukin 6 pr oduction only at the highest concentrations. 8-Bromo-cAMP and dibutyry l-cAMP stimulated interleukin 6 production to a lesser extent than vas oactive intestinal peptide and forskolin. In conclusion, we provide ev idence that vasoactive intestinal peptide increases interleukin 6 prod uction by astrocytes through the stimulation of the cAMP-protein kinas e A pathway, an effect that is reproduced by cAMP analogues. In additi on, we point out that prostaglandins are not involved in vasoactive in testinal peptide- and forskolin-mediated induction of interleukin 6 pr oduction in cultured astrocytes.