Journal of Biological Chemistry
Volume 277, Issue 17, 26 April 2002, Pages 15028-15034
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MECHANISMS OF SIGNAL TRANSDUCTION
Novel Signal Transduction Pathway Utilized by Extracellular HSP70: ROLE OF Toll-LIKE RECEPTOR (TLR) 2 AND TLR4*

https://doi.org/10.1074/jbc.M200497200Get rights and content
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Recent studies have initiated a paradigm shift in the understanding of the function of heat shock proteins (HSP). It is now clear that HSP can and do exit mammalian cells, interact with cells of the immune system, and exert immunoregulatory effects. We recently demonstrated that exogenously added HSP70 possesses potent cytokine activity, with the ability to bind with high affinity to the plasma membrane, elicit a rapid intracellular Ca2+ flux, activate NF-κB, and up-regulate the expression of pro-inflammatory cytokines in human monocytes. Here for the first time, we report that HSP70-induced proinflammatory cytokine production is mediated via the MyD88/IRAK/NF-κB signal transduction pathway and that HSP70 utilizes both TLR2 (receptor for Gram-positive bacteria) and TLR4 (receptor for Gram-negative bacteria) to transduce its proinflammatory signal in a CD14-dependent fashion. These studies now pave the way for the development of highly effective pharmacological or molecular tools that will either up-regulate or suppress HSP70-induced functions in conditions where HSP70 effects are desirable (cancer) or disorders where HSP70 effects are undesirable (arthritis and arteriosclerosis).

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Published, JBC Papers in Press, February 8, 2002, DOI 10.1074/jbc.M200497200

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This work was supported by National Institutes of Health Grants CA47407, CA31303, CA50642, and CA77465 (to S. K. C.), a Joint Center for Radiation Therapy Foundation Grant (to A. A.), National Institutes of Health Grants CA68544 and AI44122 (to P. E. A.) and the Deutsche Forschungsgemeinschaft (to M. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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To whom correspondence may be addressed: Dept. of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St. (D810), Boston, MA 02115. Tel.: 617-632-3885; Fax: 617-632-4599; E-mail: [email protected].