Deacetylase inhibition increases regulatory T cell function and decreases incidence and severity of collagen-induced arthritis

Exp Mol Pathol. 2009 Oct;87(2):99-104. doi: 10.1016/j.yexmp.2009.06.003. Epub 2009 Jul 3.

Abstract

Collagen-induced arthritis (CIA) is an established mouse model of disease with hallmarks of clinical rheumatoid arthritis. Histone/protein deacetylase inhibitors (HDACi) are known to inhibit the pathogenesis of CIA and other models of autoimmune disease, although the mechanisms responsible are unclear. Regulatory T cell (Treg) function is defective in rheumatoid arthritis. FOXP3 proteins in Tregs are present in a dynamic protein complex containing histone acetyltransferase and HDAC enzymes, and FOXP3 itself is acetylated on lysine residues. We therefore investigated the effects of HDACi therapy on regulatory T cell function in the CIA model. Administration of an HDACi, valproic acid (VPA), significantly decreased disease incidence (p<0.005) and severity (p<0.03) in CIA. In addition, VPA treatment increased both the suppressive function of CD4(+)CD25(+) Tregs (p<0.04) and the numbers of CD25(+)FOXP3(+) Tregs in vivo. Hence, clinically approved HDACi such as VPA may limit autoimmune disease in vivo through effects on the production and function of FOXP3(+) Treg cells.

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / enzymology
  • Arthritis, Experimental / immunology*
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / immunology*
  • Enzyme Inhibitors / pharmacology*
  • Flow Cytometry
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / drug effects
  • Male
  • Mice
  • Mice, Inbred DBA
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Valproic Acid / pharmacology*

Substances

  • Enzyme Inhibitors
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Histone Deacetylase Inhibitors
  • Valproic Acid
  • Histone Deacetylases