Abstracts (complete list) - Wissenschaft Online

Konrad Bode, Klaus Heeg, Alexander Dalpke
Bacterial origin histone deacetylase inhibitor butyric acid
inhibits dendritic cells
Posttranslational modifications of histones by acetylation are a major mechanism to
modify chromatin structure and gene expression in eukaryotic DNA. In a recent work we
could show that histone deacetylase (HDAC) inhibitors like trichostatin A or
suberoylanilide hydroxamic acid (SAHA) in non-apoptotic concentrations strongly inhibit
Toll-like receptor (TLR)-induced cytokine induction of dendritic cells. In the present
work we investigated whether the HDAC inhibitor butyric acid, a product of the
metabolism of some anaerobic bacteria, also inhibits dendritic cell activation by TLRs.
We can show in bone marrow derived dendritic cells that butyric acid strongly inhibits
the expression of several TLR induced cytokines like IL-12p40, IFNβ and TNFα on
protein (ELISA and FACS-analysis) and mRNA (real-time RT-PCR) level. Whereas TLR
stimulation resulted in transient histone H4 acetylation at selected regions of the IL-
12p40 promoter as shown by chromatin immunoprecipitation, butyric acid induced a
hyperacetylation of the whole IL-12p40 locus for a prolonged period. HDAC inhibitors
had no effects on upstream NFκB activation and nuclear translocation as well as on MAP
kinase signaling (immuno-blot and gel-shift) but recruitment of selected transcription
factors to the IL-12p40 promoter region was impaired in the presence of butyric acid.
The results give evidence that butyric acid affects immune cells by inhibiting HDACs.
This might indicate that butyric acid is involved in the induction of tolerance towards the
physiological bacterial flora in the mucosa of the intestine.