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J Biol Chem, Vol. 274, Issue 17, 11611-11618, April 23, 1999
B Activation and Tumor Necrosis
Factor Expression by Inhibiting IB Phosphorylation and Subsequent
Proteolysis
,,,,,
,, and
From the Extensively oxidized low density lipoprotein
(ox-LDL), a modulator of atherogenesis, down-regulates the
lipopolysaccharide (LPS)-induced activation of transcription factor
NF- Institute of Clinical Chemistry and
Pathobiochemistry, Klinikum rechts der Isar, Technical University
Munich, Ismaninger Strasse 22, 81675 München, Germany, the
¶ Department of Bioorganic Chemistry, Max-Planck-Institute of
Biochemistry, Am Klopferspitz 18a, 82152 Martinsried, Germany, the
Institute of Biochemistry, University of Graz,
Schubertstrasse 1, 8010 Graz, Austria, and the ** Institute for
Immunology, Ludwig-Maximilians-University Munich, Goethestrasse 31, 80336 München, Germany
B. We investigated whether 4-hydroxynonenal (HNE), a prominent
aldehyde component of ox-LDL, represents one of the inhibitory
substances. NF-B activation by stimuli such as LPS, interleukin
(IL)-1
, and phorbol ester, but not tumor necrosis factor (TNF), was
reversibly inhibited by HNE in a dose-dependent manner in
human monocytic cells, whereas AP-1 binding was unaffected. Using
similar HNE concentrations, LPS-induced B- and TNF or IL-8
promoter-dependent transcription was prevented.
Furthermore, pretreatment with HNE suppressed TNF production but not
lactate dehydrogenase levels. Under these conditions the binding of LPS
to monocytic cells was not significantly affected. However, induced
proteolysis of the inhibitory proteins IB-
, IB-, and, at a
later time point, IB-
was prevented. This is not due to
inhibition of the proteasome, the major proteolytic activities of which
remain unaffected, but rather to a specific prevention of the
activation-dependent phosphorylation of IB-. This is
the first report which demonstrates that HNE specifically inhibits the
NF-B/Rel system. Down-modulation of NF-B-regulated gene
expression may contribute at certain stages of atherosclerosis to low
levels of chronic inflammation and may also be involved in other
inflammatory/degenerative diseases.
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