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

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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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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