Role of heat shock protein hsp90 in formation of protective reactions in acute toxic stress.
The involvement of heat shock protein Hsp90 in pro-inflammatory response in male NMRI mice under conditions of acute toxic stress, caused by lipopolysaccharide from Gram negative bacteria, was studied using geldanamycin, a specific blocker of the activity of this protein. It is shown that the introduction of geldanamycin lowers total intoxication of the organism upon acute toxic stress caused by endotoxin. Thus, a decrease in cytokine TNF-alpha, IFN-gamma, IL-1, and IL-10 concentrations in blood serum of the geldanamycin-treated animals with acute toxic stress was found along with normalization of functional activity of nitric oxide producing peritoneal macrophages. Studying expression of receptor protein Tlr-4 as well of proteins of two signal cascades, NF-kappaB and SAPK/JNK, has shown that mechanisms of the geldanamycin protective effect are realized at the level of inhibition of Tlr-4 receptor expression, which provides for endotoxin-to-cell binding, and due to lowering the endotoxin-stimulated activation of signal cascades NF-kappaB and SAPK/JNK. The results suggest Hsp90 might be a therapeutic target in diseases accompanied by acute toxic stress.
Glushkova
O V
OV
Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia. glushckova@mail.ru
Novoselova
T V
TV
Khrenov
M O
MO
Parfenyuk
S B
SB
Lunin
S M
SM
Fesenko
E E
EE
Novoselova
E G
EG
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D007371:Interferon-gamma / Q000097:blood; D007375:Interleukin-1 / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D023382:Toxicity Tests, Acute; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007375:Interleukin-1; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; D007371:Interferon-gamma; C001277:geldanamycin