© 1997 American Heart Association, Inc.
Articles |
Dysregulation of Monocytic Nuclear Factor-
B by Oxidized Low-Density Lipoprotein
From the Institute of Clinical Chemistry and Pathobiochemistry (K.B., T.E., U.K., M.P., S.P., M.H., D.N.) and the Department of Internal Medicine I (F.J.N.), Klinikum rechts der Isar, Technical University Munich (Germany); the Institute of Clinical Chemistry (A.G., A.K.W.), Klinikum Grosshadern, Ludwig-Maximilians University Munich (Germany); the Institute of Biochemistry (C.K.), Albert-Ludwigs University, Freiburg, Germany; the Departments of Immunology and Vascular Biology (N.M.), the Scripps Research Institute, La Jolla, Calif; and Tularik Inc (P.A.B.), South San Francisco, Calif.
Correspondence to Dr Korbinian Brand, Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str 22, D-81675 München, Germany.
Abstract Nuclear factor-B (NF-B)/Rel transcription
factors may be involved in atherosclerosis, as is
suggested by the presence of activated NF-B in human
atherosclerotic lesions. The aim of the present study was to
investigate the effects of oxidized LDL (oxLDL) on the NF-B system
in human THP-1 monocytic cells as well as adherent monocytes. Our
results demonstrate that short-term incubation of these cells with
oxLDL activated p50/p65 containing NF-B dimers and induced
the expression of the target gene IL-8. This activation of NF-B was
inhibited by the antioxidant and H2O2 scavenger
pyrrolidine dithiocarbamate and the proteasome inhibitor
PSI. The oxLDL-induced NF-B activation was accompanied by an initial
depletion of IB-
followed by a slight transient increase in the
level of this inhibitor protein. In contrast, long-term
treatment with oxLDL prevented the lipopolysaccharide-induced
depletion of IB-, accompanied by an inhibition of both NF-B
activation and the expression of tumor necrosis factor- and
interleukin-1ß genes. These observations provide additional evidence
that oxLDL is a potent modulator of gene expression and suggest that
(dys)regulation of NF-B/Rel is likely to play an important role in
atherogenesis.
Key Words: nuclear factor-B • oxidized LDL • reactive oxygen intermediates • IB- • monocytes • macrophages
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