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B Activation by Blocking IB Kinase1
Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, South Korea
Gold compounds are used in the treatment of rheumatoid arthritis.
NF-
B is a transcription factor implicated in the expression of many
inflammatory genes. NF-B is activated by signal-induced
phosphorylation and subsequent degradation of inhibitory IB
(inhibitory protein that dissociates from NF-B) proteins, and a
multisubunit IB kinase (IKK) has been identified previously. We
tested the effect of various gold compounds on the activation of
NF-B and IKK in LPS-stimulated RAW 264.7 mouse macrophages. A
lipophilic gold compound, auranofin, suppressed the LPS-induced
increase of nuclear B-binding activity, degradation of IB
proteins, and IKK activation. Auranofin also blocked IKK activation
induced by TNF and PMA/ionomycin, suggesting that the target of
auranofin action is common among these diverse signal pathways. In
vitro IKK activity was suppressed by addition of hydrophilic gold
compounds, such as aurothiomalate, aurothioglucose, and
AuCl3. Other thiol-reactive metal ions such as zinc and
copper also inhibited IKK activity in vitro, and induction of IKK in
LPS-stimulated macrophages. In vitro IKK activity required the presence
of reducing agent and was blocked by addition of thiol group-reactive
agents. Two catalytic subunits of IKK complex, IKK
and IKKß, were
both inhibited by these thiol-modifying agents, suggesting the presence
of a cysteine sulfhydryl group in these subunits, which is critical for
enzyme activity. The antiinflammatory activity of gold compounds in the
treatment of rheumatoid arthritis may depend on modification of this
thiol group by gold.
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