Exogenous mammalian extracellular HSP70 reduces endotoxin manifestations at the cellular and organism levels

Abstract

In this study, we checked whether HSP70 preparations of different origins are able to protect model animals (rats) from endotoxic shock and modify the response of myeloid cells to lipopolysaccharide (LPS) challenge. It was shown that HSP70 preparations can effectively protect organisms from endotoxic shock by strongly decreasing mortality and restoring both homeostasis and various hemodynamic characteristics. At the cellular level, HSP70 preparations significantly inhibit LPS-induced reactive oxygen species production in various myeloid cells and decrease NO expression in macrophages, which is enhanced after LPS priming. In parallel, HSP70 preconditioning partially normalizes neutrophil apoptosis, which is disturbed as a result of LPS stimulation. These results suggest that the antiseptic actions of HSP70 preparations are probably realized at the level of receptor membrane complexes of myeloid cells, which represent the major target of LPS action. Taken together, our findings show that extracellular mammalian HSP70 may play an important role in innate immunity modulation and stimulation of endogenous protective mechanisms, both at the cellular and organism levels, which make this protein a promising base for the development of efficient antiseptic drugs.

Recombinant human Hsp70 protects against lipoteichoic acid-induced inflammation manifestations at the cellular and organismal levels

“…3). The results obtained are in general in agreement with the results of our previous studies on LPS-induced activation of human neutrophils (Rozhkova et al 2010).…”

“…8 Changes in the a mean arterial pressure (MAP) and b heart rate after intravenous injection of 0.9% NaCl, LTA, and LTA after rHsp70 pretreatment. Asterisk indicates statistically significant differences (P<0.05 using Kruskal-Wallis) in relation to the LTA group In recent years, abundant evidence has appeared implicating Hsps, particularly Hsp70, in the modification the immune response after introduction of various bacterial pathogens into the vasculature, including LTA and LPS (Johnson and Fleshner 2006;Yurinskaya et al 2009;Rozhkova et al 2010;Wheeler et al 2011).…”

“…We also showed that administration of Hsp70 preparations from different sources (bull muscle, camel heart, and recombinant human protein expressed in Spodoptera cells) efficiently protects blood phagocytes from LPS challenge (Rozhkova et al 2010).…”

“…The effect of rHsp70 on LTA-induced mortality Previously, our experiments demonstrated that administration of exogenous mammalian Hsp70 before LPS challenge significantly reduces the mortality rate and improves several parameters of hemostasis and hemodynamics in rats caused by E. coli-and Salmonella typhimurium-derived LPS injections (Kustanova et al 2006;Rozhkova et al 2010;Rozhkova et al 2011).…”

“…The clone containing human Hsp70 cDNA (pBlueScriptSK(+)-hsp70) was a kind gift of Prof. R. Morimoto (Northwestern University). Human hsp70 gene was subcloned in donor plasmid pFastBacHTb-hsp70 at HindIII and XhoI restriction sites under polyhedrin promoter (Rozhkova et al 2010;Merkulov et al 2011). The plasmid was subsequently used in Bac-to-Bac system (Invitrogen) in order to express human Hsp70.…”