title: Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells.
abstract: 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.
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4318, USA.
authors: Edwin F
authors: EF
authors: de Zoeten
authors: Liqing
authors: L
authors: Wang
authors: Kyle
authors: K
authors: Butler
authors: Ulf H
authors: UH
authors: Beier
authors: Tatiana
authors: T
authors: Akimova
authors: Hong
authors: H
authors: Sai
authors: James E
authors: JE
authors: Bradner
authors: Ralph
authors: R
authors: Mazitschek
authors: Alan P
authors: AP
authors: Kozikowski
authors: Patrick
authors: P
authors: Matthias
authors: Wayne W
authors: WW
authors: Hancock
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D015551:Autoimmunity; D015153:Blotting, Western; D003092:Colitis / Q000378:metabolism; D018450:Disease Progression; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000032:analysis; D018390:Gene Targeting; D006084:Graft Rejection / Q000517:prevention & control; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D023001:Transplantation Tolerance
chemical_list: D000813:Anilides; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C474316:tubacin; C553587:tubastatin A; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases