RT Journal Article
SR Electronic
T1 Herbimycin A Abrogates Nuclear Factor-κB Activation by Interacting Preferentially with the IκB Kinase β Subunit
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1344
OP 1351
DO 10.1124/mol.65.6.1344
VO 65
IS 6
A1 Shinichi Ogino
A1 Kazuhiro Tsuruma
A1 Takashi Uehara
A1 Yasuyuki Nomura
YR 2004
UL http://molpharm.aspetjournals.org/content/65/6/1344.abstract
AB NF (nuclear factor)-κB is known to be a critical transcription factor in inflammatory responses. We have reported that herbimycin A, a potent Src tyrosine kinase inhibitor, attenuates the NF-κB activation triggered by cytokines, bacterial endotoxin, and hydrogen peroxide. Accompanying the suppression by this agent, NF-κB-dependent gene expressions, such as cytokine, chemokine, and inducible-type nitric oxide, are specifically inhibited in glial cells. In the present study, we attempted to elucidate the possible target protein for herbimycin A on this pathway. We demonstrate here that herbimycin A preferentially inhibits IKK (IκB kinase)β. Furthermore, substituting alanine for the cysteine at 59 (Cys59) in IKKβ resulted in the insensitivity to herbimycin A, suggesting that this compound may interact with the Cys59 residue located near the catalytic ATP binding site. Taken together, these results indicate that herbimycin A can be considered a novel candidate for an anti-inflammatory drug agent through its specific inhibition of IKKβ, which results in prevention of the expression of NF-κB-dependent genes implicated in the pathogenesis of inflammatory responses.