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Inhibition of N-terminal ATPase on HSP90 attenuates colitis through enhanced Treg function.

Authors
  • Collins, C B
  • Aherne, C M
  • Yeckes, A
  • Pound, K
  • Eltzschig, H K
  • Jedlicka, P
  • de Zoeten, E F
Type
Published Article
Journal
Mucosal Immunology
Publisher
Springer Nature
Publication Date
Sep 01, 2013
Volume
6
Issue
5
Pages
960–971
Identifiers
DOI: 10.1038/mi.2012.134
PMID: 23321985
Source
Medline
License
Unknown

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.

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