Herbimycin A abrogates nuclear factor-κB activation by interacting preferentially with the IκB kinase β subunit

Shinichi Ogino, Kazuhiro Tsuruma, Takashi Uehara, Yasuyuki Nomura

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1344-1351
Number of pages8
JournalMolecular pharmacology
Volume65
Issue number6
DOIs
Publication statusPublished - Jun 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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