REGULATION OF INTERLEUKIN-6 PRODUCTION BY CAMP-PROTEIN KINASE-A PATHWAY IN RAT CORTICAL ASTROCYTES

In this study we analysed the involvement of the cAMP-protein kinase-A system in the regulation of interleukin 6 production by cultured cort ical astrocytes. Vasoactive intestinal peptide strongly increased, in a dose-dependent manner, interleukin 6 production. This effect was red uced when protein kinase A was blocked by KT-5720; it was not affected by calphostin C, a protein kinase C inhibitor. Forskolin caused a con centration-dependent increase in interleukin 6 release, that was also inhibited by KT-5720. Since prostaglandins are believed to play a role in interleukin 6 production, we tried to determine whether the stimul atory effects of vasoactive intestinal peptide and forskolin on cytoki ne release might be mediated by stimulation of prostaglandin productio n in cortical astrocytes. Vasoactive intestinal peptide did not increa se the production of either prostaglandin E(2) or F-2 alpha Conversely , forskolin concentration-dependently stimulated the production of bot h prostaglandins, an effect that was blocked by indomethacin. Indometh acin did not affect either vasoactive intestinal peptide- or forskolin -stimulated interleukin 6 production. To exclude the possibility that prostaglandins participate in interleukin 6 production induced by fors kolin, we tested the effect of prostaglandins E(2) and F-2 alpha on th e cytokine production. The former was completely ineffective in elicit ing the cytokine production, while prostaglandin F-2 alpha slightly in creased interleukin 6 only at the highest concentration. 8-Br-cAMP and (BU)(2)- cAMP stimulated interleukin 6 production to a lesser extent than vasoactive intestinal peptide and forskolin. In conclusion, we pr ovide evidence that vasoactive intestinal peptide increases interleuki n 6 production by astrocytes through the stimulation of the cAMP-prote in kinase-A pathway, an effect that is reproduced by cAMP analogues. I n addition, we point out that prostaglandins are not involved in vasoa ctive intestinal peptide- and forskolin-mediated induction of interleu kin 6 production in cultured astrocytes.