PT  - JOURNAL ARTICLE
AU  - Jong S. Kang
AU  - Young J. Jeon
AU  - Hwan M. Kim
AU  - Seung H. Han
AU  - Kyu-Hwan Yang
TI  - Inhibition of Inducible Nitric-Oxide Synthase Expression by Silymarin in Lipopolysaccharide-Stimulated Macrophages
AID  - 10.1124/jpet.302.1.138
DP  - 2002 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 138--144
VI  - 302
IP  - 1
4099  - http://jpet.aspetjournals.org/content/302/1/138.short
4100  - http://jpet.aspetjournals.org/content/302/1/138.full
SO  - J Pharmacol Exp Ther2002 Jul 01; 302
AB  - Silymarin, a polyphenolic flavonoid antioxidant, is known to have anti-inflammatory, hepatoprotective, and anticarcinogenic effects. In the present study, we report the inhibitory effect of silymarin on nitric oxide production and inducible nitric-oxide synthase (iNOS) gene expression in macrophages. In vivo administration of silymarin attenuated nitric oxide production by peritoneal macrophages in lipopolysaccharide (LPS)-treated mice. Silymarin also dose dependently suppressed the LPS-induced production of nitric oxide in isolated mouse peritoneal macrophages and RAW 264.7, a murine macrophage-like cell line. Moreover, iNOS mRNA and its protein expression were completely abrogated by silymarin in LPS-stimulated RAW 264.7 cells. To further investigate the mechanism responsible for the inhibition of iNOS gene expression by silymarin, we examined the effect of silymarin on LPS-induced nuclear factor-κB (NF-κB)/Rel activation, which regulates various genes involved in immune and inflammatory response. In RAW 264.7 cells, the LPS-induced DNA binding activity of NF-κB/Rel was significantly inhibited by silymarin, and this effect was mediated through the inhibition of the degradation of inhibitory factor-κB. Silymarin also inhibited tumor necrosis factor-α-induced NF-κB/Rel activation, whereas okadaic acid-induced NF-κB/Rel activation was not affected. NF-κB/Rel-dependent reporter gene expression was also suppressed by silymarin in LPS-stimulated RAW 264.7 cells. Further study showed that silymarin suppressed the production of reactive oxygen species generated by H2O2 in RAW 264.7 cells. Collectively, these results suggest that silymarin inhibits nitric oxide production and iNOS gene expression by inhibiting NF-κB/Rel activation. Furthermore, the radical-scavenging activity of silymarin may explain its inhibitory effect on NF-κB/Rel activation. The American Society for Pharmacology and Experimental Therapeutics