Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells.
Schauber. Jürgen J; Iffland. Konrad K; Frisch. Susanne S; Kudlich. Theodor T; Schmausser. Bernd B; Eck. Matthias M; Menzel. Thomas T; Gostner. Andrea A; Lührs. Hardi H; Scheppach. Wolfgang W
Key Findings
- GI cancer cells normally do not produce LL‑37, but HDAC inhibitors can induce its expression
- Butyrate causes a time‑dependent increase in LL‑37 linked to acetylation of histone H4 and the protein HMGN2
- Blocking the MEK‑ERK signaling pathway stops the HDAC‑inhibitor‑driven rise in LL‑37
Practical Outcomes
- Increasing dietary fiber or resistant starch to raise gut butyrate levels might help stimulate LL‑37 production and support gut barrier function, but the evidence is from cell experiments only. No specific dosage or protocol can be drawn yet, and more human studies are needed before applying this as a health hack.
Summary
The study shows that chemicals called HDAC inhibitors, like the natural compound butyrate (found in high‑fiber foods), can turn on the production of the antimicrobial peptide LL‑37 in colon, stomach and liver cancer cells. This effect depends on changes to proteins that control gene activity and needs a specific cell signaling pathway. While it hints that boosting butyrate could enhance gut immunity, the work was done in cell lines, not people, so direct recommendations are limited.
Abstract
Histone-deacetylase (HDAC) -inhibitors enhance acetylation of core proteins and this is linked to formation of transcriptionally active chromatin in various cells. In this study, the effect of HDAC inhibitors (butyrate, trichostatin A (TSA)) on the expression of the cathelicidin LL-37 in colon, gastric and hepatocellular cells was investigated. LL-37 expression was assessed in colon, gastric and hepatocellular cancer cells after treatment with HDAC-inhibitors. In parallel, histone H4 and HMGN2, a non-histone protein, acetylation was evaluated. In addition, the intracellular signalling pathway MEK-ERK was explored. In contrast to normal colon epithelial cells, gastrointestinal cancer cells lacked LL-37 expression. LL-37 was induced following treatment with HDAC-inhibitors in all investigated cell lines. This induction was time-dependent in butyrate-treated cells while TSA exerted a transient effect. Induction of LL-37 by butyrate was paralleled by acetylation of the histone H4 and the non-histone HMGN2. Again, TSA resulted in transient acetylation. Furthermore, inhibition of MEK-ERK blocked HDAC inhibitor-induced LL-37 expression in colonic and gastric cells. We have previously shown that butyrate induces LL-37 in colon epithelial cells. In the present study, we demonstrate that cathelicidin expression is modulated by HDAC-inhibitors in various gastrointestinal cells including gastric and hepatocellular cells. This is paralleled by changes in the acetylation of distinct core proteins suggesting a common regulatory mechanism of cathelicidin LL-37 regulation in these cells.
Study Information
pubmed
2004
10.1016/j.molimm.2004.05.005