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Zinc Signals Are Essential for Lipopolysaccharide-Induced Signal Transduction in Monocytes¹

Hajo Haase^*, Julia L. Ober-Blöbaum, Gabriela Engelhardt^*, Silke Hebel^*, Antje Heit, Holger Heine and Lothar Rink^2,*

^* Institute of Immunology and Institute for Biomedical Engineering, Department of Cell Biology, Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, Aachen, Germany; Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany; and Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany

Cytosolic alterations of calcium ion concentrations are an integral part of signal transduction. Similar functions have been hypothesized for other metal ions, in particular zinc (Zn²⁺), but this still awaits experimental verification. Zn²⁺ is important for multiple cellular functions, especially in the immune system. Among other effects, it influences formation and secretion of pro-inflammatory cytokines, including TNF-. Here we demonstrate that these effects are due to a physiological signaling system involving intracellular Zn²⁺ signals. An increase of the intracellular zinc ion concentration occurs upon stimulation of human leukocytes with Escherichia coli, LPS, Pam₃CSK₄, TNF-, or insulin, predominantly in monocytes. Chelating this zinc signal with the membrane permeable zinc-specific chelator TPEN (N,N,N',N'-tetrakis-(2-pyridyl-methyl)ethylenediamine) completely blocks activation of LPS-induced signaling pathways involving p38 MAPK, ERK1/2, and NF-B, and abrogates the release of proinflammatory cytokines, including TNF-. This function of Zn²⁺ is not limited to monocytes or even the immune system, but seems to be another generalized signaling system based on intracellular fluctuations of metal ion concentrations, acting parallel to Ca²⁺.

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 study was supported by Grant HA4318/3-2 from The Deutsche Forschungsgemeinschaft and a grant from the START Program of the medical faculty, Rheinisch-Westfälische Technische Hochschule Aachen University.

² Address correspondence and reprint requests to Dr. Lothar Rink, Institute of Immunology, RWTH Aachen University Hospital, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail address: LRink{at}ukaachen.de

³ Abbreviations used in this paper: TRIF, Toll/IL-1R domain–containing adaptor-inducing IFN-β; PKC, protein kinase C; pNPP, p-nitrophenol phosphate; PTP, protein tyrosine phosphatase; eGFP, enhanced GFP; IKK, IB kinase.

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