Induction of histidine decarboxylase in macrophages inhibited by the novel NF-kappaB inhibitor (-)-DHMEQ.
Histamine often causes inflammation, and this amine is produced by histidine decarboxylase (HDC). We found that (-)-DHMEQ, an NF-kappaB inhibitor, inhibited lipopolysaccharide (LPS)-induced histamine production and HDC induction in mouse macrophage cell line RAW264.7. However, as there is no kappaB site in the HDC promoter, we studied the mechanism of inhibition. Knockdown of the transcription factor C/EBPbeta reduced the HDC expression in LPS-treated cells. (-)-DHMEQ inhibited the C/EBPbeta transcriptional activity in a reporter assay and in an electrophoresis mobility shift assay. But it did not inhibit the in vitro binding of C/EBPbeta to DNA. It also did not lower the nuclear amount of C/EBPbeta. On the other hand, the addition of recombinant p65, a component of NF-kappaB, enhanced the activity of C/EBPbeta acting as a cofactor in vitro. Then, we found that (-)-DHMEQ lowered the nuclear amount of p65. Thus, inhibition of the C/EBPbeta activity by (-)-DHMEQ would be due to a reduction in the amount of nuclear p65, which has a co-activator activity for C/EBPbeta that is essential for the HDC induction. (-)-DHMEQ may be useful as an anti-inflammatory agent by lowering the histamine production in the body.
Suzuki
Eriko
E
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan. eriboeribo@hotmail.com
Ninomiya
Yoko
Y
Umezawa
Kazuo
K
D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology*; D006632:Histamine / Q000378:metabolism; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors; D015533:Transcriptional Activation / Q000187:drug effects
D001549:Benzamides; D022782:CCAAT-Enhancer-Binding Protein-beta; D003512:Cyclohexanones; D008070:Lipopolysaccharides; D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C464444:dehydroxymethylepoxyquinomicin; D006632:Histamine; D006640:Histidine Decarboxylase