Serotonin 5-HT2A Receptor Activation Inhibits Cytokine-stimulated Inducible Nitric Oxide Synthase in C6 Glioma Cellsa

C6-glioma cells endogenously express both 5-HT2A receptors and inducible nitric oxide synthase (iNOS). iNOS can be induced by transcriptional activation to produce nitric oxide (NO) in response to a challenge with the pro-inflammatory cytokines TNF-alpha and IFN-gamma. Experiments were conducted to determine whether 5-HT2A receptor activation could modify the production of NO in response to the inducing agents. 1 muM DOI produced a dose-dependent inhibition of the cytokine-inducted nitrite levels of 40% which was inhibited by spiperone and ritanserin. In addition, the DOI-mediated decrease was prevented by the PKC inhibitor chelerythrine (100 nM). The effectiveness of DOI was lost when added more than two hours after the addition of inducing agent, suggesting that DOI was regulating iNOS at the level of transcription rather than post-translationally. We suggest that there is a link between the serotonergic system and NO-mediated immune responses in the brain.