Repression of interferon-gamma-induced inducible nitric oxide synthase (iNOS) gene expression in microglia by sodium butyrate is mediated through specific inhibition of ERK signaling pathways.

We have reported recently that sodium butyrate suppressed IFN-gamma, but not the LPS-mediated induction of nitric oxide and TNF-alpha in microglia via the specific inhibition of NF-kappaB. In order to further determine the upstream signaling mechanism involved in the IFN-gamma-specific down-regulation of iNOS by sodium butyrate in microglia, this study investigated the effect of sodium butyrate on the MAP kinase activities. Sodium butyrate significantly repressed the phosphorylation of ERK induced by IFN-gamma, but had little effect on that induced by LPS. This suggests that sodium butyrate suppresses the IFN-gamma-induced iNOS expression by inhibiting the ERK to NF-kappaB pathway. In addition, it was found that sodium butyrate suppressed the IFN-gamma-induced interferon regulatory factor 1 (IRF-1) expression via the inhibition of ERK. Therefore, the ERK signaling pathway appears to play a key role in the sodium butyrate-mediated down-regulation of iNOS in the IFN-gamma-stimulated microglia.