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J. Biol. Chem., Vol. 276, Issue 34, 32008-32015, August 24, 2001
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From the Deutsches Krebsforschungszentrum Heidelberg, Division of
Toxicology and Cancer Risk Factors, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Sulforaphane (SFN), an aliphatic isothiocyanate,
is a known cancer chemopreventive agent. Aiming to investigate
anti-inflammatory mechanisms of SFN, we here report a potent decrease
in lipopolysaccharide (LPS)-induced secretion of pro-inflammatory and
pro-carcinogenic signaling factors in cultured Raw 264.7 macrophages
after SFN treatment, i.e. NO, prostaglandin E2,
and tumor necrosis factor
Nuclear Factor
B Is a Molecular Target for
Sulforaphane-mediated Anti-inflammatory Mechanisms*
. SFN did not directly interact with NO,
nor did it inhibit inducible nitric-oxide synthase enzymatic activity.
Western blot analyses revealed time- and dose-dependent
reduction of LPS-induced inducible nitric-oxide synthase as well as
Cox-2 protein expression, which was suppressed at the transcriptional
level. To reveal the target of SFN beyond its anti-inflammatory action,
we performed electrophoretic mobility shift assay analyses of
transcription factor-DNA binding. Consequently, nuclear factor 
B
(NF-B), a pivotal transcription factor in LPS-stimulated
pro-inflammatory response, was identified as the key mediator. SFN
selectively reduced DNA binding of NF-B without interfering with
LPS-induced degradation of the inhibitor of NF-B nor with nuclear
translocation of NF-B. Because SFN can interact with thiol groups by
dithiocarbamate formation, it may impair the redox-sensitive DNA
binding and transactivation of NF-B. Sulforaphane could either
directly inactivate NF-B subunits by binding to essential Cys
residues or interact with glutathione or other redox regulators like
thioredoxin and Ref-1 relevant for NF-B function. Our data provide
novel evidence that anti-inflammatory mechanisms contribute to
sulforaphane-mediated cancer chemoprevention.
*
This work was supported by Verein zur Förderung der
Krebsforschung in Deutschland e.V. These data were presented in
part at the 90th Annual Meeting of the American Association
of Cancer Research, April 10-14, 1999 in Philadelphia, PA (68).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom requests for reprints should be addressed: DKFZ
Heidelberg, C0202 Chemoprevention, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Tel.: 49-6221-42-33-06; Fax:
49-6221-42-33-59; E-mail: c.gerhauser@dkfz.de.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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