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HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine

Nature Medicine volume 6, pages 435–442 (2000)Cite this article

Abstract

Here, we demonstrate a previously unknown function for the 70-kDa heat-shock protein (HSP70) as a cytokine. HSP70 bound with high affinity to the plasma membrane, elicited a rapid intracellular calcium flux, activated nuclear factor (NF)-κB and upregulated the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in human monocytes. Furthermore, two different signal transduction pathways were activated by exogenous HSP70: one dependent on CD14 and intracellular calcium, which resulted in increased IL-1β, IL-6 and TNF-α; and the other independent of CD14 but dependent on intracellular calcium, which resulted in an increase in TNF-α but not IL-1β or IL-6. These findings indicate that CD14 is a co-receptor for HSP70-mediated signaling in human monocytes and are indicative of an previously unrecognized function for HSP70 as an extracellular protein with regulatory effects on human monocytes, having a dual role as chaperone and cytokine.

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Figure 1: HSP70 specifically binds to the surface membrane of human monocytes.
Figure 2: Exogenous HSP70 upregulates the expression of pro-inflammatory cytokines.
Figure 3: Exogenous HSP70 induces the phosphorylation of I-κBα and a rapid calcium flux.
Figure 4: Involvement of the CD14 receptor in HSP70-induced cytokine expression.

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Acknowledgements

We thank P.E. Auron (Harvard Institute of Medicine) for review of the manuscript; T. Blake and P. Fischer (Merck Research Laboratories) and L. Popova (Dana-Farber Cancer Institute) for technical assistance; and The Kraft Family Blood Center (Dana-Farber Cancer Institute) for the freshly drawn peripheral venous blood. This work was supported by National Institutes of Health Grants CA47407, CA31303, CA50642, CA77465 (to S.K.C.) and in part by UNCF/Merck Science Initiative (to A.A.)

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Author notes

  1. Evelyn A. Kurt-Jones & Robert W. Finberg

    Present address: Department of Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts, 01655, USA

Authors and Affiliations

  1. Department of Adult Oncology, Dana-Farber Cancer Institute,Harvard Medical School, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Alexzander Asea, Evelyn A. Kurt-Jones, Mary Ann Stevenson, Robert W. Finberg & Stuart K. Calderwood

  2. Department of Cancer Biology, Dana-Farber Cancer Institute,Harvard Medical School, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Stine-Kathrein Kraeft & Lan Bo Chen

  3. Department of Immunology Research, Merck Research Laboratories, 126 East Lincoln Street, Rahway, 07065, New Jersey, USA

    Gloria C. Koo

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Correspondence to Stuart K. Calderwood.

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Asea, A., Kraeft, SK., Kurt-Jones, E. et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6, 435–442 (2000). https://doi.org/10.1038/74697

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