Inhibition of Hsp90 attenuates inflammation in endotoxin‐induced uveitis

Poulaki, Vassiliki; Iliaki, Eirini; Mitsiades, Nicholas; Mitsiades, Constantine S.; Paulus, Yannis M.; Bula, Deisy V.; Gragoudas, Evangelos S.; Miller, Joan W.

doi:10.1096/fj.06-7637com

Cited by 73 publications

(68 citation statements)

References 54 publications

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“…Previous studies have reported therapeutic benefit of targeting Hsp90 in the rodent inflammatory autoimmune disease models uveitis, experimental autoimmune encephalitis, and rat arthritis, using both ansamycin-derived inhibitors and a fully synthetic Hsp90 inhibitor (8,(14)(15)(16). In this report, we demonstrate that the synthetic Hsp90 inhibitor EC144 is potent and selective and is efficacious in an inflammatory mouse model of endotoxin shock and an autoimmune mouse CIA model.…”

Section: Discussionmentioning

confidence: 59%

“…It has been previously reported that exposure of various cell types to geldanamycin resulted in surface CD14 downmodulation (6,9,14). Because CD14 is a coreceptor for LPS binding to TLR4, modulation of CD14 by Hsp90 inhibition was a possible mechanism for the EC144-induced general decrease in the LPS response.…”

Section: Ec144 Inhibits Tlr4 Signaling In Raw 2647 By Blocking Mapk mentioning

confidence: 95%

“…In vivo Hsp90 inhibition with 17-AAG in a rat LPS-induced uveitis model has been shown to suppress multiple manifestations of LPS treatment, including retinal leukocyte adhesion, cytokine production, and PI3K activity (14). To determine whether the selective small-molecule Hsp90 inhibitor EC144 could block LPS-induced responses in vivo, EC144 was tested in a mouse LPS shock model that generates an acute systemic inflammatory response dependent on TNF-a (28,30).…”

Section: Ec144 Is Active In Vivo and Inhibits Lps-induction Of Tnf-amentioning

confidence: 99%

“…In rats, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a derivative of geldanamycin, was shown to prevent the development of LPS-induced autoimmune uveitis by suppressing activation of multiple signaling molecules that mediate the TLR-4-induced proinflammatory cytokine response in retinal cells (14), and geldanamycin has been shown to suppress adjuvant-induced arthritis (8). Similarly, Dello Russo et al (15) demonstrated that 17-AAG could inhibit proinflammatory TLR4 stimulation in vitro and dramatically reduce disease incidence and severity in myelin oligodendrocyte glycoproteinpeptide-induced experimental autoimmune encephalitis.…”

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confidence: 99%

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

Yun¹,

Harning²,

Giza³

et al. 2011

The Journal of Immunology

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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.

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Section: Discussionmentioning

confidence: 59%

Section: Ec144 Inhibits Tlr4 Signaling In Raw 2647 By Blocking Mapk mentioning

confidence: 95%

Section: Ec144 Is Active In Vivo and Inhibits Lps-induction Of Tnf-amentioning

confidence: 99%

mentioning

confidence: 99%

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

Yun¹,

Harning²,

Giza³

et al. 2011

The Journal of Immunology

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“…The receptor tyrosine kinase KIT, which regulates mast cell actions, appears to be a sensitive client for Hsp90 with relevance to multiple diseases (22). In vivo efficacy of Hsp90 inhibitors in preclinical models of arthritis, sepsis, and uveitis supports the relevance of Hsp90 inhibition observed in vitro (23,24).…”

mentioning

confidence: 83%

Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis

Rice¹,

Veal²,

Fadden³

et al. 2008

Arthritis & Rheumatism

126

111

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Objective. To evaluate the ability of SNX-7081, a novel small molecule inhibitor of Hsp90, to block components of inflammation, including cytokine production, protein kinase activity, and angiogenic signaling. A close analog was evaluated in preclinical in vivo models of rheumatoid arthritis (RA).Methods. SNX-7081 binding to Hsp90 was characterized in Jurkat cells and RA synovial fibroblasts (RASFs). Inhibition of NF-B nuclear translocation was evaluated in cellular systems, using lipopolysaccharide (LPS), tumor necrosis factor ␣, or interleukin-1␤ stimulation. Suppression of cytokine production in THP-1 cells, human umbilical vein endothelial cells, and RASFs was studied. Disruption of MAPK signaling cascades by SNX-7081 following growth factor stimulation was assessed. SNX-7081 was tested in 2 relevant angiogenesis assays: platelet-derived growth factor activation of fibroblasts and LPS-induced nitric oxide (NO) release in J774 macrophages. A close analog, SNX-4414, was evaluated in rat collagen-induced arthritis and adjuvant-induced arthritis, following oral treatment.Results. SNX-7081 showed strong binding affinity to Hsp90 and expected induction of Hsp70. NF-B nuclear translocation was blocked by SNX-7081 at nanomolar concentrations, and cytokine production was potently inhibited. Growth factor activation of ERK and JNK signaling was significantly reduced by SNX-7081. NO production was also sharply inhibited. In animal models, SNX-4414 fully inhibited paw swelling and improved body weight. Scores for inflammation, pannus formation, cartilage damage, and bone resorption returned to normal.Conclusion. The present results demonstrate that a small molecule Hsp90 inhibitor can impact inflammatory disease processes. The strong in vivo efficacy observed with SNX-4414 provides preclinical validation for consideration of Hsp90 inhibitors in the treatment of RA.

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Pharmacologic heat shock protein 70 induction confers cytoprotection against inflammation in gliovascular cells

Kacimi

Yenari

2015

Glia

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Inhibition of the 90 kDa heat-shock protein (HSP90) leads to upregulation of the 70 kDa inducible heat shock protein (HSP70). HSP70 has previously been shown to be neuroprotective and anti-inflammatory. Geldanamycin (GA) and other HSP90 inhibitors have emerged as promising therapeutic agents in cancer, presumably due to their ability to upregulate HSP70. However, the effects of HSP90 inhibition in brain inflammation are still unclear. We investigate the effect of a panel of HSP90 inhibitors on endotoxin-activated microglia and eventual protection from brain derived endothelial cells. Prior studies have shown that GA protects brain cells from oxidative stress. We show here that when astrocytes or microglial BV2 cells were pretreated with GA or other HSP90 inhibitors, endotoxin-induced cell death was reduced in co-cultures of BV2 microglia and brain derived endothelial cells (bEND.3). Endotoxin stimulated BV2 cells led to increased nitric oxide (NO) and inducible nitric oxide synthase (iNOS) which was prevented by treatment with all HSP90 inhibitors. HSP90 inhibitors also prevented LPS -induced BV2 cell death. We also found that HSP90 inhibition blocked nuclear translocation of NF-κB and attenuated IκBα degradation, and inhibited LPS-activated JAK-STAT phosphorylation. We show that pharmacologic inhibition of HSP90 with subsequent HSP70 induction protects cells that comprise the cerebral vasculature against cell death due to pro-inflammatory stimuli. This approach may have therapeutic potential in neurological conditions with an inflammatory component.

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Inhibition of Hsp90 attenuates inflammation in endotoxin‐induced uveitis

Cited by 73 publications

References 54 publications

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

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

Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis

Pharmacologic heat shock protein 70 induction confers cytoprotection against inflammation in gliovascular cells

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