Suppressive effects of ansamycins on inducible nitric oxide synthase expression and the development of experimental autoimmune encephalomyelitis.
The production of nitric oxide by the inflammatory isoform of nitric oxide synthase (NOS2) in brain glial cells is thought to contribute to the causes and development of neurological diseases and trauma. We previously demonstrated that activation of a heat shock response (HSR) by hyperthermia reduced NOS2 expression in vitro, and in vivo attenuated the clinical and histological symptoms of the demyelinating disease experimental autoimmune encephalomyelitis (EAE; Heneka et al. [2001] J. Neurochem. 77:568-579). Benzoquinoid ansamycins are fungal-derived antibiotics with tyrosine kinase inhibitory properties, and which also induce a HSR by allowing activation of HS transcription factor HSF1. We now show that two members of this class of drugs (geldanamycin and 17-allylamino-17-demethoxygeldanamycin) also induce a HSR in primary rat astrocytes and rat C6 glioma cells. Both drugs dose-dependently reduced nitrite accumulation, NOS2 steady-state mRNA levels, and the cytokine-dependent activation of a rat 2.2-kB NOS2 promoter construct stably expressed in C6 cells. These inhibitory effects were partially reversed by quercetin, a bioflavonoid which prevents HSF1 binding to DNA and thus attenuates the HSR. Ansamycins increased mRNA levels of the inhibitory IkappaBalpha protein, suggesting that inhibition of NFkappaB activation could contribute to their suppressive effects. Finally, in C57BL/6 mice actively immunized to develop EAE, a single injection of geldanamycin at 3 days after immunization reduced disease onset by over 50%. These results indicate that ansamycins can exert potent anti-inflammatory effects on brain glial cells which may provide therapeutic benefit in neuroinflammatory diseases.
Murphy
Patricia
P
Department of Anesthesiology, University of Illinois, 1819 West Polk Street, Chicago, IL 60612, USA.
Sharp
Anthony
A
Shin
Joseph
J
Gavrilyuk
Vitaliy
V
Dello Russo
Cinzia
C
Weinberg
Guy
G
Sharp
Frank R
FR
Lu
Aigang
A
Heneka
Michael T
MT
Feinstein
Douglas L
DL
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D016227:Benzoquinones; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects* / Q000502:physiology; D020672:I-kappa B Proteins; D007371:Interferon-gamma / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D020672:I-kappa B Proteins; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D011809:Quinones; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D017828:Rifabutin; D009569:Nitric Oxide; C112765:tanespimycin; D007371:Interferon-gamma; D011794:Quercetin; D019001:Nitric Oxide Synthase; D011505:Protein-Tyrosine Kinases; C001277:geldanamycin