Journal
JOURNAL OF IMMUNOLOGY
Volume 181, Issue 9, Pages 6491-6502Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.9.6491
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Funding
- Deutsche Forschungsgemeinschaft [HA4318/3-2]
- Rheinisch-Westfalische Technische Hochschule Aachen University
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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 proinflammatory cytokines, including TNF-alpha. 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, Pam(3)CSK(4), TNF-alpha, 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-kappa B, and abrogates the release of proinflammatory cytokines, including TNF-alpha. 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 Journal of Immunology, 2008, 181: 6491-6502.
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