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  • Title: The heat-shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis.
    Author: Dello Russo C, Polak PE, Mercado PR, Spagnolo A, Sharp A, Murphy P, Kamal A, Burrows FJ, Fritz LC, Feinstein DL.
    Journal: J Neurochem; 2006 Dec; 99(5):1351-62. PubMed ID: 17064348.
    Abstract:
    The heat-shock response (HSR), a highly conserved cellular response, is characterized by rapid expression of heat-shock proteins (HSPs), and inhibition of other synthetic activities. The HSR can attenuate inflammatory responses, via suppression of transcription factor activation. A HSR can be induced pharmacologically by HSP90 inhibitors, through activation of the transcription factor Heat Shock Factor 1 (HSF1). In the present study we characterized the effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a less toxic derivative of the naturally occurring HSP90 inhibitor geldanamycin, on glial inflammatory responses and the development of experimental autoimmune encephalomyelitis. In primary enriched glial cultures, 17-AAG dose dependently reduced lipopolysaccharide-dependent expression and activity of inducible nitric oxide synthase, attenuated interleukin (IL)-1beta expression and release, increased inhibitor of kappaB protein levels, and induced HSP70 expression. 17-AAG administration to mice immunized with myelin oligodendrocyte glycoprotein peptide prevented disease onset when given at an early time, and reduced clinical symptoms when given during ongoing disease. T cells from treated mice showed a reduced response to immunogen re-stimulation, and 17-AAG reduced CD3- and CD28-dependent IL-2 production. Together, these data suggest that HSP90 inhibitors could represent a new approach for therapeutic intervention in autoimmune diseases such as multiple sclerosis.
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