Inhibitory effects of heat shock protein 90 blockade on proinflammatory human Th1 and Th17 cell subpopulations

Background: heat 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. findings: using 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-aα,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. conclusions: our results further support the potential use of hsp90 inhibitors in patients with autoimmune diseases where uncontrolled th1 or th17 activation frequently occurs. © 2014 tukaj et al.; licensee biomed central ltd.