Tanshinone IIA inhibits LPS-induced NF-κB activation in RAW 264.7 cells:: Possible involvement of the NIK-IKK, ERK1/2, p38 and JNK pathways

Nuclear factor kappa B (NF-kappa B) activation by NF-kappa B-inducing kinase (NIK)-I kappa B alpha kinase (IKK) pathway and mitogen-activated protein kinases (MAPKs) pathway are important in inflammation. We recently found that the tanshinone IIA, a diterpene isolated from Salvia miltiorrhiza (S. miltiorrhiza), reduced the production of pro-inflammatory mediators in RAW 264.7 cells stimulated with lipopolysaccharide (LPS). However, little is known about the inhibitory mechanisms of tanshinone IIA on the production of pro-inflammatory mediators. To investigate the inhibitory mechanism, we determined the inhibitory effects of tanshinone IIA on the activation of NF-kappa B and I kappa B alpha phosphorylation, and also examined phosphorylation of NIK and IKK as well as the activation of MAPKs such as p38 MAPK (p38), extracellular signal-regulated kinases 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) in RAW 264.7 cells stimulated with LPS. Tanshinone IIA inhibited NF-kappa B-DNA complex, NF-kappa B binding activity, and the phosphorylation Of I kappa B alpha in a dose dependent manner. Tanshinone HA also inhibited the translocation of NF-kappa B from cytosol to nucleus. Moreover, the phosphorylation of NIK and IKK as well as the phosphorylation of p38, ERK1/2, and JNK in the LPS-stimulated RAW 264.7 cells were suppressed by the tanshinone IIA in a dose dependent manner. These results suggest that tanshinone IIA may inhibit LPS-induced I kappa B alpha degradation and NF-kappa B activation via suppression of the NIK-IKK pathway as well as the MAPKs (p38, ERK1/2, and JNK) pathway in RAW 264.7 cells and these properties may provide a potential mechanism that explains the anti-inflammatory activity of tanshitione IIA. (c) 2006 Elsevier B.V. All rights reserved.