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Hsp72 Induces Inflammation and Regulates Cytokine Production in Airway Epithelium through a TLR4- and NF-B-Dependent Mechanism¹

Margaret A. Chase^*, Derek S. Wheeler^*,, Kristin M. Lierl^*, Valerie S. Hughes^*, Hector R. Wong^*, and Kristen Page^2,*,

^* Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229; and the Department of Pediatrics, University of Cincinnati, Cincinnati OH 45267

Heat shock proteins are generally regarded as intracellular proteins acting as molecular chaperones; however, Hsp72 is also detected in the extracellular compartment. Hsp72 has been identified in the bronchoalveolar lavage fluid (BALF) of patients with acute lung injury. To address whether Hsp72 directly activated airway epithelium, human bronchial epithelial cells (16HBE14o-) were treated with recombinant Hsp72. Hsp72 induced a dose-dependent increase in IL-8 expression, which was inhibited by the NF-B inhibitor parthenolide. Hsp72 induced activation of NF-B, as evidenced by NF-B trans-activation and by p65 RelA and p50 NF-B1 binding to DNA. Endotoxin contamination of the Hsp72 preparation was not responsible for these effects. Next, BALB/c mice were challenged with a single intratracheal inhalation of Hsp72 and killed 4 h later. Hsp72 induced significant up-regulation of KC, TNF-, neutrophil recruitment, and myeloperoxidase in the BALF. A similar challenge with Hsp72 in TLR4 mutant mice did not stimulate the inflammatory response, stressing the importance of TLR4 in Hsp72-mediated lung inflammation. Last, cultured mouse tracheal epithelial cells (MTEC) from BALB/c and TLR4 mutant and wild-type mice were treated ex vivo with Hsp72. Hsp72 induced a significant increase in KC expression from BALB/c and wild-type MTEC in an NF-B-dependent manner; however, TLR4 mutant MTEC had minimal cytokine release. Taken together, these data suggest that Hsp72 is released and biologically active in the BALF and can regulate airway epithelial cell cytokine expression in a TLR4 and NF-B-dependent mechanism.

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 the National Institutes of Health Grants HL075568 (to K.P.), GM077432 (to D.S.W.), and GM061723 (to H.R.W.).

² Address correspondence and reprint requests to Dr. Kristen Page, Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, ML7006, Cincinnati OH 45229. E-mail address: kristen.page{at}cchmc.org

³ Abbreviations used in this paper: ALI, acute lung injury; BALF, bronchoalveolar lavage fluid; PAF, platelet-activating factor; MTEC, mouse tracheal epithelial cell.

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