Alpha-lipoic acid modulates NF-kappaB activity in human monocytic cells by direct interaction with DNA

The constitutive activity of the redox-sensitive transcription factor, NF-kappaB, which regulates the production of many inflammatory cytokines and adhesion molecules, appears to be up-regulated in an age-associated manner and it is thought this might contribute to the increased incidence of chronic inflammatory conditions observed with increasing age. As some antioxidants have demonstrated protective effects against rheumatoid arthritis, we are investigating the effects of vitamin E, vitamin C and alpha-lipoic acid (ALA) on NF-kappaB activity and on the expression of intracellular adhesion molecule (ICAM)-1. MonoMac6 cells (a human monocytic cell line) stimulated with tumour necrosis factor-alpha (TNF-alpha) were treated with antioxidants at physiological achievable levels and ICAM-1 mRNA levels investigated. Both vitamin E and vitamin C had no effect on ICAM-1 expression at the doses used, but ALA reduced the TNF-alpha-stimulated ICAM-1 expression in a dose-dependent manner, to levels observed in unstimulated cells. Alpha-lipoic acid also reduced NF-kappaB activity in these cells in a dose-dependent manner. Addition of ALA to the binding reaction of nuclear extract with DNA prior to gel-shift analysis showed that it caused inhibition at this level. These initial results suggest that antioxidant modulation of monocyte activity might have potential benefits in inhibiting the dysregulated activity of redox-sensitive transcription factors that occurs with increasing age.