title: Inhibition of N-terminal ATPase on HSP90 attenuates colitis through enhanced Treg function.
abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory condition thought to reflect a failure of the enteral immune system to adequately regulate itself. Inflammatory stress drives upregulation of heat-shock proteins (HSPs), including the pro-inflammatory chaperone, HSP90. This protein sequesters the transcription factor, heat-shock factor 1 (HSF1) in the cytoplasm preventing transcription of a number of anti-inflammatory proteins. We hypothesized that inhibition of HSP90 would exert an anti-inflammatory effect and thereby attenuate intestinal inflammation in murine models of IBD. Inhibition of HSP90 with 17-allylaminogeldanamycin (17-AAG) reduced inflammation in acute dextran sodium sulfate and chronic CD45RB(High) colitis models coinciding with increased interleukin (IL)-10 production in the colon. Regulatory T cells (Tregs) from mice treated with 17-AAG demonstrated significantly greater suppressive capacity in vitro abolished in HSF1-/- or IL-10-/- cells. Finally, Tregs treated with 17-AAG exhibited increased nuclear localization of HSF1 with resultant upregulation of HSF1 response genes, including HSP70, HSP90 and IL-10.
authors: Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors: C B
authors: CB
authors: Collins
authors: C M
authors: CM
authors: Aherne
authors: A
authors: A
authors: Yeckes
authors: K
authors: K
authors: Pound
authors: H K
authors: HK
authors: Eltzschig
authors: P
authors: P
authors: Jedlicka
authors: E F
authors: EF
authors: de Zoeten
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology*; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate / Q000008:administration & dosage; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D047029:Lactams, Macrocyclic; D014157:Transcription Factors; D016753:Interleukin-10; C112765:tanespimycin; D016264:Dextran Sulfate; D017493:Leukocyte Common Antigens; D000251:Adenosine Triphosphatases