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Role of Heat Shock Protein Hsp90 in Formation of Protective Reactions in Acute Toxic Stress

O. V. Glushkova*, T. V. Novoselova, M. O. Khrenov, S. B. Parfenyuk, S. M. Lunin, E. E. Fesenko, and E. G. Novoselova

Institute of Cell Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia; fax: (496) 733-0509; E-mail: glushckova@mail.ru

* To whom correspondence should be addressed.

Received December 16, 2009; Revision received January 15, 2010
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.
KEY WORDS: heat shock protein 90, geldanamycin, toxic stress, lipopolysaccharide, NF-κB and SAPK/JNK signal pathways, cytokines, nitric oxide, Tlr-4

DOI: 10.1134/S0006297910060040