tubacin and Colitis

Foxp3(+) T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3(+) Tregs express multiple histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression, and protein function. Pan-HDAC inhibitors developed for oncologic applications enhance Treg production and Treg suppression function but have limited nononcologic utility given their broad actions and various side effects. We show, using HDAC6-deficient mice and wild-type (WT) mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully major histocompatibility complex (MHC)-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein heat shock protein 90 (HSP90). Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection.

Topics: Anilides; Animals; Autoimmunity; Blotting, Western; Colitis; Disease Progression; Flow Cytometry; Forkhead Transcription Factors; Gene Targeting; Graft Rejection; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; HSP90 Heat-Shock Proteins; Hydroxamic Acids; Immunoprecipitation; Indoles; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Microarray Analysis; Molecular Sequence Data; Polymerase Chain Reaction; T-Lymphocytes, Regulatory; Transplantation Tolerance