Abstract: Inflammatory bowel diseases are chronic intestinal inflammatory diseases thought to reflect a dysregulated immune response. Although antibody-based inhibition of tumor necrosis factor-α (TNF-α) has provided relief to many inflammatory bowel diseases patients, these therapies are either ineffective in a patient subset or lose their efficacy over time, leaving an unmet need for alternatives. Given the critical role of the heat shock response in regulating inflammation, this study proposed to define the impact of selective inhibition of heat shock protein 90 (HSP90) on intestinal inflammation. Using multiple preclinical mouse models of inflammatory bowel diseases, we demonstrate a potent anti-inflammatory effect of selective inhibition of the HSP90 C-terminal ATPase using the compound novobiocin. Novobiocin-attenuated dextran sulfate sodium-induced colitis and CD45RBhigh adoptive-transfer colitis through the suppression of inflammatory cytokine secretion, including TNF-α. In vitro assays demonstrate that CD4+ T cells treated with novobiocin produced significantly less TNF-α measured by intracellular cytokine staining and by enzyme-linked immunosorbent assay. This corresponded to significantly decreased nuclear p65 translocation by Western blot and a decrease in nuclear factor-κB luciferase activity in Jurkat T cells. Finally, to verify the anti-TNF action of novobiocin, 20-week-old TNFΔARE mice were treated for 2 weeks with subcutaneous administration of novobiocin. This model has high levels of circulating TNF-α and exhibits spontaneous transmural segmental ileitis. Novobiocin treatment significantly reduced inflammatory cell infiltrate in the ileal lamina propria. HSP90 inhibition with novobiocin offers a novel method of inflammatory cytokine suppression without potential for the development of tolerance that limits current antibody-based methods.
Article first Published online 18 February 2014
*Mucosal Inflammation Program, Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Digestive Health Institute, Aurora, Colorado;
†Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado; and
‡Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado.
Reprints: Edwin F. de Zoeten, MD, PhD, Mucosal Inflammation Program, Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Digestive Health Institute, Anschutz Medical Campus, 13123 East 16th Avenue, B290, Aurora, CO (e-mail: edwin.DeZoeten@childrenscolorado.org).
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Supported by the Grant: K08DK080189 (E.F.Z.) and CCFA-3768 (C.B.C.), and UL1 RR025780 (E.F.Z. and C.B.C.).
The authors have no conflicts of interest to disclose.
Received November 12, 2013
Accepted December 28, 2013