Suppression by a sesquiterpene lactone from Carpesium divaricatum of inducible nitric oxide synthase by inhibiting nuclear factor-kappaB activation

초록

Excessive nitric oxide (NO) produced by inducible NO synthase (iNOS) acts as a causative regulator in various inflammatory disease states. Carpesium divaricatum has been used in Korean traditional herbal medicine for its antipyretic, analgesic, vermifugic, and anti-inflammatory properties. We investigated the molecular mechanism for the suppression of lipopolysaccharide/interferon-gamma (LPS/IFN gamma)-induced NO production in RAW 264.7 macrophages by the sesquiterpene lactone 2 beta ,5-epoxy-5,10-dihydroxy-6 alpha -angeloyloxy-9 beta -isobutyloxy-germacran-8 alpha ,12-olide (C-l), which has been identified recently as a new compound from C. divaricatum. C-1 decreased NO production in LPS/IFN-gamma -stimulated RAW 264.7 cells in a concentration-dependent manner, with an IC50 of approximately 2.16 muM; however, it had no direct effect on the iNOS activity of fully IPS/IFN-gamma -stimulated RAW 264.7 cells. Furthermore, treatment with C-1 led to a decrease in iNOS protein and mRNA. These effects appear to be due to inhibition of nuclear factor-kappaB (NF-kappaB) activation through a mechanism involving stabilization of the NF-kappaB/inhibitor of the kappaB (I-kappaB) complex, since inhibition of NF-kappaB DNA binding activity by C-1 was accompanied by a parallel reduction of nuclear translocation of subunit p65 of NF-kappaB and I-kappaB alpha degradation. Taken together, the results suggest that the ability of C-1 to inhibit iNOS gene expression may be responsible, in part, for its anti-inflammatory effects.

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