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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenosine Triphosphatases / metabolism*
-
Animals
-
Benzoquinones / pharmacology
-
Cell Nucleus / metabolism*
-
Cells, Cultured
-
Colitis / chemically induced
-
Colitis / drug therapy
-
Colitis / immunology*
-
Cytoplasm / metabolism*
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism*
-
Dextran Sulfate / administration & dosage
-
HSP90 Heat-Shock Proteins / metabolism*
-
Heat Shock Transcription Factors
-
Humans
-
Interleukin-10 / genetics
-
Interleukin-10 / metabolism
-
Lactams, Macrocyclic / pharmacology
-
Leukocyte Common Antigens / metabolism
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Protein Transport / drug effects
-
Protein Transport / genetics
-
T-Lymphocytes, Regulatory / drug effects
-
T-Lymphocytes, Regulatory / immunology*
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
Substances
-
Benzoquinones
-
DNA-Binding Proteins
-
HSF1 protein, human
-
HSP90 Heat-Shock Proteins
-
Heat Shock Transcription Factors
-
Lactams, Macrocyclic
-
Transcription Factors
-
Interleukin-10
-
tanespimycin
-
Dextran Sulfate
-
Leukocyte Common Antigens
-
Adenosine Triphosphatases