Role of heat shock protein Hsp90 in formation of protective reactions in acute toxic stress

• Published in: Biochemistry (Moscow) 2010-06, Vol.75 (6), p.702-707
• Main Authors: Glushkova, O. V., Novoselova, T. V., Khrenov, M. O., Parfenyuk, S. B., Lunin, S. M., Fesenko, E. E., Novoselova, E. G.
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics; Antibiotics, Antineoplastic - pharmacology; Benzoquinones - pharmacology; Biochemistry; Biological products; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Endotoxins; Heat shock proteins; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - physiology; Interferon; Interferon-gamma - blood; Interleukin-1 - blood; Interleukin-10 - blood; Lactams, Macrocyclic - pharmacology; Life Sciences; Lipopolysaccharides - toxicity; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Microbiology; Mitogens; NF-kappa B - metabolism; Nitric oxide; Nitric Oxide - metabolism; Rodents; Signal Transduction; Toll-Like Receptor 4 - metabolism; Toxicity Tests, Acute; Toxicology; Tumor necrosis factor; Tumor Necrosis Factor-alpha - blood
• ISSN: 0006-2979; 1608-3040
• DOI: 10.1134/S0006297910060040

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-α, IFN-γ, 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-κB 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-κB and SAPK/JNK. The results suggest Hsp90 might be a therapeutic target in diseases accompanied by acute toxic stress.