Abstract
BackgroundHeat shock protein 90 (Hsp90), a chaperone that regulates activity of many client proteins responsible for cellular growth, differentiation, and apoptosis, has been proposed as an important clinical and preclinical therapeutic target in a number of malignancies and autoimmune diseases, respectively. In this study, we evaluated the effects of pharmacological Hsp90 inhibition on human proinflammatory T cell responses.FindingsUsing anti-CD3 antibody-stimulated human peripheral blood mononuclear cell cultures, we observed that Hsp90 inhibition by non-toxic concentrations of the geldanamycin derivative 17-DMAG significantly blocked T cell proliferation, reduced IFN-γ and IL-17 expression on CD4+ T lymphocytes, and arrested secretion of proinflammatory IFN-γ, TNF-α, and IL-17, cytokines characteristic of Th1 and Th17 cells, respectively. These effects were associated with inhibition of NF-kB activity, upregulation of Hsp70 protein expression, and disruption of T cell-specific nonreceptor tyrosine kinase Lck activation.ConclusionsOur results further support the potential use of Hsp90 inhibitors in patients with autoimmune diseases where uncontrolled Th1 or Th17 activation frequently occurs.
Highlights
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that is exploited by malignant cells to support activated oncoproteins, including many cancer-associated kinases and transcription factors, but has been shown to exert potent immunomodulatory actions [1,2].Several pieces of evidence show that Th1 and Th17 cells are pathophysiologically associated with several autoimmune diseases and that Hsp90 activity is required for IFN-γ and IL-17 signaling in these cell types, respectively [3,4,5]
Our results further support the potential use of Hsp90 inhibitors in patients with autoimmune diseases where uncontrolled Th1 or Th17 activation frequently occurs
We show that blockade of Hsp90 by the geldanamycin derivative 17-DMAG leads to inhibition of T cell proliferation, suppression of IFN-γ and IL-17 expression on CD4+ T cells, and attenuation of secretion of proinflammatory IFN-γ, TNF-α, and IL-17, cytokines characteristic of Th1 and Th17 cells, respectively
Summary
Several pieces of evidence show that Th1 and Th17 cells are pathophysiologically associated with several autoimmune diseases and that Hsp activity is required for IFN-γ and IL-17 signaling in these cell types, respectively [3,4,5]. Based on these findings and the observations that Hsp plays important roles in antigen presentation, activation of lymphocytes, macrophages, and dendritic cells [2], we and others claim that pharmacological inhibition of Hsp is a promising therapy to ameliorate inflammatory cascades in autoimmune diseases [6,7,8,9,10,11]. We evaluated the effects of pharmacological Hsp inhibition on human proinflammatory T cell responses
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