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 up-regulation of heat-shock proteins (HSP) 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-AAG reduced inflammation in acute DSS and chronic CD45RBHigh colitis models coinciding with increased 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 up-regulation of HSF1 response genes including HSP70, HSP90 and IL-10.