Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells

Mol Immunol. 2004 Jul;41(9):847-54. doi: 10.1016/j.molimm.2004.05.005.

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.

Methods: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / metabolism*
  • Butyrates / pharmacology
  • Cathelicidins
  • Gastrointestinal Neoplasms / metabolism
  • Gastrointestinal Tract / drug effects*
  • Gastrointestinal Tract / metabolism
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology
  • MAP Kinase Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Phylogeny
  • Signal Transduction / physiology

Substances

  • Antimicrobial Cationic Peptides
  • Butyrates
  • Cathelicidins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • ropocamptide
  • trichostatin A
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases