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* Department of Critical Care Medicine, University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213;
Division of Critical Care Medicine, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, and Children’s Hospital Research Foundation, Cincinnati, OH, 45229; and
Division of Critical Care Medicine, C. S. Mott Children’s Hospital, University of Michigan, Ann Arbor, MI 48109
Recent data suggest that heat shock protein-70 (HSP-70), an intracellular protein, can exist in the extracellular compartment and signal through the CD14/TLR4 pathway. In this study, we tested the hypothesis that extracellular HSP-70 induces endotoxin (LPS) tolerance. Using human monocyte cell line (THP-1), initial dose-response experiments were conducted to determine a subthreshold concentration of HSP-70 that does not induce NF-
B activity. Differentiated THP-1 cells were preconditioned with subthreshold concentration (0.03 µg/ml HSP-70) for 18 h, followed by LPS stimulation (1 µg/ml) for 4 h. Preconditioning with HSP-70 decreased subsequent LPS-mediated NF-B-dependent promoter activity and was accompanied by significant decreases of supernatant TNF levels. Furthermore, human monocytes isolated from human volunteers, subsequently preconditioned with HSP-70, demonstrated LPS tolerance as evidenced by abrogated supernatant TNF levels. Additional experiments were conducted to exclude the possibility of endotoxin contamination of HSP-70 by boiling HSP-70 at 100°C for 1 h or preconditioning with equivalent concentrations of endotoxin as present in the HSP-70 preparation. These experiments indicated that induction of tolerance was not secondary to endotoxin contamination. Neutralization experiments with an anti-HSP-70 Ab confirmed the specificity of HSP-70 in tolerance induction. Preconditioning with HSP-70 attenuated cytosolic degradation of inhibitor B-
and inhibited activation of inhibitor B kinase following LPS stimulation. HSP-70 preconditioning decreased phosphorylation of the p65 subunit of NF-B following LPS stimulation. These data suggest a novel role for extracellular HSP-70 in modifying mononuclear cell responses to subsequent LPS challenge.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants K08GM076344 (to R.K.A.), R01GM66839 (to T.P.S.), and R01GM061723 (to H.R.W.).
2 Address correspondence and reprint requests to Dr. Rajesh K. Aneja, Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213. E-mail address: anejar{at}upmc.edu
3 Abbreviations used in this paper: HSP, heat shock protein; IKK, IB kinase.
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