Induction of histidine decarboxylase in macrophages inhibited by the novel NF-κB inhibitor (−)-DHMEQ

Histamine often causes inflammation, and this amine is produced by histidine decarboxylase (HDC). We found that (−)-DHMEQ, an NF-κB inhibitor, inhibited lipopolysaccharide (LPS)-induced histamine production and HDC induction in mouse macrophage cell line RAW264.7. However, as there is no κB site in the HDC promoter, we studied the mechanism of inhibition. Knockdown of the transcription factor C/EBPβ reduced the HDC expression in LPS-treated cells. (−)-DHMEQ inhibited the C/EBPβ transcriptional activity in a reporter assay and in an electrophoresis mobility shift assay. But it did not inhibit the in vitro binding of C/EBPβ to DNA. It also did not lower the nuclear amount of C/EBPβ. On the other hand, the addition of recombinant p65, a component of NF-κB, enhanced the activity of C/EBPβ acting as a cofactor in vitro. Then, we found that (−)-DHMEQ lowered the nuclear amount of p65. Thus, inhibition of the C/EBPβ activity by (−)-DHMEQ would be due to a reduction in the amount of nuclear p65, which has a co-activator activity for C/EBPβ that is essential for the HDC induction. (−)-DHMEQ may be useful as an anti-inflammatory agent by lowering the histamine production in the body.