The heat-shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis

J Neurochem. 2006 Dec;99(5):1351-62. doi: 10.1111/j.1471-4159.2006.04221.x. Epub 2006 Oct 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Anti-Inflammatory Agents / pharmacology
  • Benzoquinones / pharmacology*
  • Central Nervous System / drug effects
  • Central Nervous System / immunology
  • Central Nervous System / physiopathology
  • Disease Models, Animal
  • Encephalitis / drug therapy*
  • Encephalitis / immunology
  • Encephalitis / physiopathology
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gliosis / drug therapy*
  • Gliosis / immunology
  • Gliosis / physiopathology
  • HSP72 Heat-Shock Proteins / drug effects
  • HSP72 Heat-Shock Proteins / metabolism
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • I-kappa B Proteins / drug effects
  • I-kappa B Proteins / metabolism
  • Immunosuppressive Agents / pharmacology
  • Interleukin-1beta / drug effects
  • Interleukin-1beta / metabolism
  • Interleukin-2 / metabolism
  • Lactams, Macrocyclic / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase Type II / drug effects
  • Nitric Oxide Synthase Type II / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • Treatment Outcome

Substances

  • Anti-Inflammatory Agents
  • Benzoquinones
  • Enzyme Inhibitors
  • HSP72 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • I-kappa B Proteins
  • Immunosuppressive Agents
  • Interleukin-1beta
  • Interleukin-2
  • Lactams, Macrocyclic
  • tanespimycin
  • Nitric Oxide Synthase Type II