DYSREGULATION OF MONOCYTIC NUCLEAR FACTOR-KAPPA-B BY OXIDIZED LOW-DENSITY-LIPOPROTEIN

Nuclear factor-kappa B (NF-kappa B)/Rel transcription factors may be i nvolved in atherosclerosis, as is suggested by the presence of activat ed NF-kappa B in human atherosclerotic lesions. The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the N F-kappa B system in human THP-1 monocytic cells as well as adherent mo nocytes. Our results demonstrate that short-term incubation of these c ells with oxLDL activated p50/p65 containing NF-kappa B dimers and ind uced the expression of the target gene IL-8. This activation of NF-kap pa B was inhibited by the antioxidant and H2O2 scavenger pyrrolidine d ithiocarbamate and the proteasome inhibitor PSI. The oxLDL-induced NF- kappa B activation was accompanied by an initial depletion of I kappa B-alpha followed by a slight transient increase in the level of this i nhibitor protein. In contrast, long-term treatment with oxLDL prevente d the lipopolysaccharide-induced depletion of I kappa B-alpha, accompa nied by an inhibition of both NF-kappa B activation and the expression of tumor necrosis factor-alpha and interleukin-1 beta genes. These ob servations provide additional evidence that oxLDL is a potent modulato r of gene expression and suggest that (dys)regulation of NF-kappa B/Re l is likely to play an important role in atherogenesis.