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

      Nature medicine

      Antigens, CD14, immunology, Calcium, Cells, Cultured, Cytokines, physiology, DNA-Binding Proteins, metabolism, HSP70 Heat-Shock Proteins, pharmacology, Humans, I-kappa B Proteins, Interleukin-1, biosynthesis, Interleukin-6, Monocytes, cytology, drug effects, NF-kappa B, antagonists & inhibitors, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha

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          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)-kappaB and upregulated the expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta 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-1beta, IL-6 and TNF-alpha; and the other independent of CD14 but dependent on intracellular calcium, which resulted in an increase in TNF-alpha but not IL-1beta 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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          Author and article information

          Journal
          10742151
          10.1038/74697

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