Inhibition of lipopolysaccharide-induced expression of inducible nitric oxide synthase and tumor necrosis factor-α by 2′-hydroxychalcone derivatives in RAW 264.7 cells

Abstract

In cultures of the murine macrophage cell line RAW 264.7, effects of four 2′-hydroxychalcone derivatives, 2′-hydroxy-4′-methoxychalcone (compound 1), 2′,4-dihydroxy-4′-methoxychalcone (compound 2), 2′,4-dihydroxy-6′-methoxychalcone (compound 3) and 2′-hydroxy-4,4′-dimethoxychalcone (compound 4), on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and tumor necrosis factor (TNF)-α were examined. Compounds 1, 2 and 3 at 3–30 μM inhibited the production with almost the same potency. Compound 4 showed no inhibitory activity. Compounds 1, 2 and 3 at 3–30 μM inhibited the LPS-induced expression of inducible nitric oxide synthase (iNOS) and TNF-α mRNA. To clarify the mechanism involved, effects of compounds 1, 2 and 3 on the activation of nuclear factor (NF)-κB and activator protein-1 (AP-1) were examined. Both the LPS-induced activation of NF-κB and AP-1 were blocked by compounds 1, 2 and 3 at 3–30 μM. Moreover, the three compounds at such concentrations inhibited the LPS-induced IκB degradation and the phosphorylation of c-jun N-terminal kinase (JNK) and c-jun. These findings suggest that the inhibition of the LPS-induced production of NO and TNF-α by the 2′-hydroxychalcone derivatives is due to the inhibition of NF-κB and AP-1 activations.