EC144, a Synthetic Inhibitor of Heat Shock Protein 90, Blocks Innate and Adaptive Immune Responses in Models of Inflammation and Autoimmunity

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone involved in folding and stabilizing multiple intracellular proteins that have roles in cell activation and proliferation. Many Hsp90 client proteins in tumor cells are mutated or overexpressed oncogenic proteins driving cancer cell growth, leading to the acceptance of Hsp90 as a potential therapeutic target for cancer. Because several signal transduction molecules that are dependent on Hsp90 function are also involved in activation of innate and adaptive cells of the immune system, we investigated the mechanism by which inhibiting Hsp90 leads to therapeutic efficacy in rodent models of inflammation and autoimmunity. EC144, a synthetic Hsp90 inhibitor, blocked LPS-induced TLR4 signaling in RAW 264.7 cells by inhibiting activation of ERK1/2, MEK1/2, JNK, and p38 MAPK but not NF-κB. Ex vivo LPS-stimulated CD11b+ peritoneal exudate cells from EC144-treated mice were blocked from phosphorylating tumor progression locus 2, MEK1/2, and ERK1/2. Consequently, EC144-treated mice were resistant to LPS administration and had suppressed systemic TNF-α release. Inhibiting Hsp90 also blocked in vitro CD4+ T cell proliferation in mouse and human MLRs. In vivo, semitherapeutic administration of EC144 blocked disease development in rat collagen-induced arthritis by suppressing the inflammatory response. In a mouse collagen-induced arthritis model, EC144 also suppressed disease development, which correlated with a suppressed Ag-specific Ab response and a block in activation of Ag-specific CD4+ T cells. Our results describe mechanisms by which blocking Hsp90 function may be applicable to treatment of autoimmune diseases involving inflammation and activation of the adaptive immune response.

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

“…Recently, T cells from mice treated with an HSP90 inhibitor showed reduced responsiveness to activating antigens in the collagen induced arthritis model. 25 Han et al 11 found that an inhibitor for the endoplasmic reticulum homologue of HSP90, gp96, reduced both the CD4 1 memory T cells and activated CD4 1 T cells in the spleen and lymph nodes. The effects of HSP90 inhibition on T-cell populations might be The effect of heat shock protein 90 inhibition in lupus mice SK Shimp III et al 263 explained by the fact that stimulation of the T-cell receptor leading to T-cell activation requires HSP90 to stabilize lymphocyte-specific protein tyrosine kinase (Lck) in order to initiate activation.…”

“…24 Recently, a synthetic HSP90 inhibitor (EC144) was found to decrease disease severity in mouse and rat models of induced arthritis. 25 Also, the gp96 inhibitor, (S)-methyl 2-(4,6-dimethoxypyrimidine-2-yloxy)-3-methylbutanoate, was shown to reduce the severity of SLE-like disease in transgenic mice. 11 MRL/lpr mice serve as a model to study human SLE as they exhibit similar manifestations to the human disease including glomerulonephritis (GN), vasculitis and arthritis.…”

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

“…Pharmacological inhibition of Hsp90 function has therefore emerged as a promising method to ameliorate inflammatory cascades, as it has been demonstrated in various experimental mouse models of autoimmune diseases, including autoimmune encephalomyelitis (Dello Russo et al 2006), rheumatoid arthritis (Rice et al 2008;Yun et al 2011), and systemic lupus erythematosus (Han et al 2010;Shimp et al 2012a). Our own recent research work showed that, by downregulating T cell responses, this kind of treatment is also effective in mice with the experimentally induced subepidermal autoimmune blistering skin disease epidermolysis bullosa acquisita (Kasperkiewicz et al 2011).…”

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

“…Given the similarity between tumor cells and leukocytes with respect to their amoeboid migration (18), HSP90 could also be involved in interstitial leukocyte migration; thus, targeting HSP90 could ameliorate inflammation-associated diseases. As has been reported, HSP90 is considered to be a promising druggable target for treating inflammatory and neurodegenerative diseases (19,20). Therefore, the development of novel HSP90 inhibitors is necessary for the HSP90-based therapy of inflammation-associated diseases, including MS.…”