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Herbimycin A Abrogates Nuclear Factor-B Activation by Interacting Preferentially with the IB Kinase Subunit

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan

NF (nuclear factor)-B 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-B activation triggered by cytokines, bacterial endotoxin, and hydrogen peroxide. Accompanying the suppression by this agent, NF-B-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 (IB kinase). Furthermore, substituting alanine for the cysteine at 59 (Cys59) in IKK 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 IKK, which results in prevention of the expression of NF-B-dependent genes implicated in the pathogenesis of inflammatory responses.

Received October 31, 2003; accepted March 1, 2004.

Address correspondence to: Prof. Yasuyuki Nomura, Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. E-mail: nomura{at}pharm.hokudai.ac.jp

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