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

Rice, John W.; Veal, James M.; Fadden, R. Patrick; Barabasz, Amy; Partridge, Jeffrey M.; Barta, Thomas E.; Dubois, Laura G.; Huang, Kenneth H.; Mabbett, Sarah R.; Silinski, Melanie A Rehder; Steed, Paul M.; Hall, Steven E.

doi:10.1002/art.24047

Cited by 126 publications

(124 citation statements)

References 49 publications

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Tukaj

Grüner

Zillikens

et al. 2014

Cell Stress and Chaperones

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Bullous pemphigoid (BP) is the most common subepidermal autoimmune blistering skin disease characterized by autoantibodies against the hemidesmosomal proteins BP180 and BP230. The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses, and recent evidence suggests that it represents a novel treatment target in autoimmune bullous diseases. The aim of the study was to investigate the contribution of Hsp90 to the proinflammatory cytokine production in keratinocytes induced by autoantibodies to BP180 from BP patient serum. HaCaT cells were treated with purified human BP or normal IgG in the absence or presence of the Hsp90 blocker 17-DMAG and effects on viability, interleukin 6 (IL-6) and IL-8 (cytokines critical for BP pathology), NFκB (their major transcription factor), and Hsp70 (marker of effective Hsp90 inhibition and potent negative regulator of inflammatory responses) were investigated. We found that BP IgG stimulated IL-6 and IL-8 release from HaCaT cells and that non-toxic doses of 17-DMAG inhibited this IL-8, but not IL-6 secretion in a dose-and time-dependent fashion.

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Section: Introductionmentioning

confidence: 99%

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

Tukaj

Grüner

Zillikens

et al. 2014

Cell Stress and Chaperones

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“…20 Recently, GA was also used to reduce inflammation as a treatment for rheumatoid arthritis. 21 In addition to GA and 17-DMAG, HSP90 can also be inhibited by novobiocin, epigallocatechin gallate, cisplatin and others. 22,23 These alternative inhibitors differ from GA and 17-DMAG in that they exert additional effects on cellular mechanisms beyond the blockade of HSP90.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Fas lpr /Fas lpr (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/ lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8 1 T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.

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“…IKK and JAK play, respectively, a key role in the activation of nuclear factor-kB (NF-kB) and signal transducers and activators of transcription (STAT), major transcription factors that regulate the expression of many genes involved in inflammation (10,11). This overall prompted the notion of HSP90 as a molecular target of interest for the treatment of several immunological and inflammatory disorders (12,13). So far, most clinical trials of HSP90 inhibitors have focused on cancer therapy (14).…”

mentioning

confidence: 99%

“…Preclinical data implicate HSP90 as a promising anti-inflammatory target in rheumatoid arthritis, systemic lupus erythematosus, uveitis, liver injury, and cardiovascular disease models (12,(15)(16)(17)(18). In diabetic animals, HSP90 inhibition improved insulin sensitivity (19), high-fat diet-induced renal failure (20), and neurodegeneration (21), but the underlying mechanisms involved in these antidiabetic actions are not well defined.…”

mentioning

confidence: 99%

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

et al. 2015

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Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes-associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Treatment of diabetic mice with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG, 2 and 4 mg/kg, 10 weeks) improved renal function, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leukocyte infiltration, and fibrosis), and expression of proinflammatory and profibrotic genes. Furthermore, DMAG significantly reduced atherosclerotic lesions and induced a more stable plaque phenotype, characterized by lower content of lipids, leukocytes, and inflammatory markers, and increased collagen and smooth muscle cell content. Mechanistically, the renoprotective and antiatherosclerotic effects of DMAG are mediated by the induction of protective HSP70 along with inactivation of nuclear factor-kB (NF-kB) and signal transducers and activators of transcription (STAT) and target gene expression, both in diabetic mice and in cultured cells under hyperglycemic and proinflammatory conditions. In conclusion, HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications.

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

Cited by 126 publications

References 49 publications

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

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

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

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

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