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Keywords:

  • Alternative activation;
  • Arginase-1;
  • Gene regulation;
  • Histone deacetylases (HDACs);
  • Macrophages;
  • STAT6;
  • Trichostatin A (TSA)

The amount of arginine available at inflammatory loci is a limiting factor for the growth of several cells of the immune system. IL-4-induced activation of macrophages produced arginase-1, which converts arginine into ornithine, a precursor of polyamines and proline. Trichostatin A (TSA), a pan-inhibitor of histone deacetylases (HDACs), inhibited IL-4-induced arginase-1 expression. TSA showed promoter-specific effects on the IL-4-responsive genes. While TSA inhibited the expression of arginase-1, fizz1, and mrc1, other genes, such as ym,1 mgl1, and mgl2, were not affected. The inhibition of arginase-1 occurred at the transcriptional level with the inhibition of polymerase II binding to the promoter. IL-4 induced STAT6 phosphorylation and binding to DNA. These activities were not affected by TSA treatment. However, TSA inhibited C/EBPβ DNA binding. This inhibitor induced acetylation on lysine residues 215–216, which are critical for DNA binding. Finally, using macrophages from STAT6 KO mice we showed that STAT6 is required for the DNA binding of C/EBPβ. These results demonstrate that the acetylation/deacetylation balance strongly influences the expression of arginase-1, a gene of alternative activation of macrophages. These findings also provide a molecular mechanism to explain the control of gene expression through deacetylase activity.