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The heat‐shock protein 90 inhibitor 17‐allylamino‐17‐demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis
Author(s) -
Russo Cinzia Dello,
Polak Paul E.,
Mercado Pilar R.,
Spagnolo Alessandra,
Sharp Anthony,
Murphy Patricia,
Kamal Adeela,
Burrows Francis J.,
Fritz Lawrence C.,
Feinstein Douglas L.
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04221.x
Subject(s) - experimental autoimmune encephalomyelitis , myelin oligodendrocyte glycoprotein , heat shock protein , hsf1 , geldanamycin , myelin basic protein , immunology , hsp90 inhibitor , tumor necrosis factor alpha , biology , hsp90 , inflammation , hsp70 , myelin , endocrinology , biochemistry , central nervous system , gene
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)‐1β expression and release, increased inhibitor of κB 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.