Post-transcriptional inhibition of lipopolysaccharide-induced expression of inducible nitric oxide synthase by Go6976 in murine microglia

Glia in the brain respond to various toxins with an increased expression of inducible nitric oxide synthase (iNOS) and an increased production of nitr ic oxide (NO). Hen, we report that lipopolysaccharide (LPS)-induced express ion of iNOS was down-regulated post-transcriptionally through the destabili zation of iNOS mRNA by the indolocarbazole compound, Go6976, in murine micr oglia. This Go6976 effect is specific for iNOS since tumor necrosis factor alpha was unaffected by the compound. Interestingly, the post-transcription al effects ascribed to Go6976 were not observed with other inhibitors of pr otein kinase A, C (PKC), G, or protein tyrosine kinases. Instead, these kin ases appear to affect the iNOS/NO system at the transcriptional level. In t he past, Go6976 has been reported to be a rather specific inhibitor of PKC in vitro. Results from our experiments, through prolonged treatment with ph orbol esters and with the various PKC inhibitors including phorbol ester-in sensitive PKC isotype inhibitor, suggest that the Go6976-mediated post-tran scriptional regulation of iNOS gene expression and NO production in microgl ia is not mediated through its reputed effects on PKC activity. Since the e ffects of various neurotoxins and certain neurodegenerative diseases may be manifested through alterations in the iNOS/NO system, post-transcriptional control of this system may represent a novel strategy for therapeutic inte rvention. (C) 2000 Elsevier Science B.V. All rights reserved.