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- Title
The heat-shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis.
- Authors
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.
- 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)-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.
- Subjects
ENCEPHALOMYELITIS; ASTROCYTES; INTERLEUKINS; MICROGLIA; MULTIPLE sclerosis; NITRIC oxide
- Publication
Journal of Neurochemistry, 2006, Vol 99, Issue 5, p1351
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2006.04221.x