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J Biol Chem, Vol. 275, Issue 15, 10925-10929, April 14, 2000
From the Department of Microbiology, New York University School of
Medicine, New York, New York 10016
Sodium salicylate inhibits activation of the
transcription factor NF-
ACCELERATED PUBLICATION
Inhibition of I
B Kinase Activity by Sodium Salicylate in
Vitro Does Not Reflect Its Inhibitory Mechanism in Intact
Cells*
and
ek§
B by blocking the phosphorylation and
degradation of the NF-B inhibitor IB
. We previously
demonstrated that salicylate inhibits IB degradation induced by
tumor necrosis factor (TNF) but not by interleukin-1 (IL-1) and
implicated p38 mitogen-activated protein kinase activation by
salicylate in the inhibition of TNF-induced IB phosphorylation.
Both TNF and IL-1 rapidly activate the IB kinase (IKK) complex,
containing the catalytic subunits IKK and IKK
, which directly
phosphorylates IB proteins. Others have recently suggested that
salicylate inhibits NF-B activation by directly binding to IKK.
To clarify the mechanism whereby salicylate inhibits IKK activity, we
examined its effects upon cytokine-induced IKK activity in intact cells
and in vitro. Treatment of intact cells with salicylate
inhibited TNF-induced but not IL-1-induced IKK activity, and this
inhibition was prevented by the p38 inhibitor SB203580. In contrast,
inhibition of IKK activity by salicylate in vitro was
neither selective for TNF nor affected by SB203580. In
vitro, salicylate treatment comparably inhibited the kinase activity of overexpressed IKK and IKK and also decreased p38 kinase activity. Therefore, direct inhibition of IKK activity in
vitro does not reflect the inhibitory mechanism of salicylate in
intact cells, which involves interference with TNF signaling.
*
This work was supported in part by National Institutes of
Health Grants R01-CA75071 and R35-CA49731.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.
Supported by a Medical Scientist Training Program fellowship from
National Institutes of Health Training Grant 5T32-GM07308.
§
To whom correspondence should be addressed: Dept. of Microbiology,
New York University School of Medicine, 550 First Ave., New York, NY
10016. Tel.: 212-263-6756; Fax: 212-263-7933; E-mail: jan.
vilcek@med.nyu.edu.
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