title: The heat-shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis.
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.
authors.affiliation: Department of Anesthesiology, University of Illinois, and Jesse Brown Veteran's Affairs Research Division, Chicago, Illinois 60612, USA.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Dello Russo
authors.forename: Paul E
authors.initials: PE
authors.lastname: Polak
authors.forename: Pilar R
authors.initials: PR
authors.lastname: Mercado
authors.forename: Alessandra
authors.initials: A
authors.lastname: Spagnolo
authors.forename: Anthony
authors.initials: A
authors.lastname: Sharp
authors.forename: Patricia
authors.initials: P
authors.lastname: Murphy
authors.forename: Adeela
authors.initials: A
authors.lastname: Kamal
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Burrows
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Fritz
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology*; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005911:Gliosis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D050884:HSP72 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D050884:HSP72 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D007376:Interleukin-2; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D052247:Nitric Oxide Synthase Type II