2-Amino-3-methylimidazo[4,5-f]quinoline inhibits nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells by blocking p38 kinase activation

We show that 2-amino-3-methyl imidazo[4,5-f] quinoline (IQ), a heterocyclic amine, significantly inhibits nitric oxide (NO) production in lipopolysacc haride (LPS)-stimulated macrophages. The decrease in NO production was foun d to correlate well with a decrease in inducible NO synthase (iNOS) mRNA ex pression as demonstrated by Northern blot analysis. Treatment of RAW 264.7 cells with IQ selectively inhibited the activation of N kappa -KB/Rel, an i mportant transcription factor of iNOS gene expression, while neither AP-1 n or Oct was affected by IQ. Since iNOS transcription has been shown recently to be under the control of the p38 kinase signaling cascade, we assessed t he effect of IQ on p38 kinase activation. Treatment of RAW 264.7 with IQ in hibited LPS-stimulated p38 kinase phosphorylation in a dose-related manner. IQ also inhibited the p38 kinase activity. Collectively, this series of ex periments indicates that IQ inhibits LPS-induced expression of iNOS gene in RAW 264.7 cells. Based on our findings, the most likely mechanism that can account for this biological effect involves the negative regulation of NF- kappaB/Rel and p38 kinase pathway. (C) 2000 Elsevier Science Ireland Ltd. A ll rights reserved.