Inhibition of Lethality in Endotoxin Challenged Mice Treated With Zinc Chloride

Snyder, S.L.; Walker, R.I.

doi:10.1016/b978-0-12-588250-7.50040-3

Cited by 22 publications

(31 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although low concentrations act synergistically with LPS (19,20), higher ones inhibit the production of these cytokines (15)(16)(17)(18). Zinc cannot only reduce mRNA expression of proinflammatory cytokines in cultured cells (15), it also inhibits LPS-mediated toxicity in mice (16,30). Although the molecular mechanism that leads to the inhibition by high zinc concentrations was found to be based on a modulation of cGMP signaling (17,18), only few data exist regarding the mechanism furthering proinflammatory events.…”

Section: Discussionmentioning

confidence: 99%

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

Haase

Ober‐Blöbaum

Engelhardt

et al. 2008

The Journal of Immunology

254

243

View full text Add to dashboard Cite

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-α. 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-α, 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-κB, and abrogates the release of proinflammatory cytokines, including TNF-α. 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+.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Haase

Ober‐Blöbaum

Engelhardt

et al. 2008

The Journal of Immunology

254

243

View full text Add to dashboard Cite

show abstract

“…One major group of genes affected by zinc status is related to inflammation, and zinc can directly affect several kinds of inflammatory diseases, including rheumatoid arthritis, diabetes, asthma, and sepsis (6)(7)(8)(9)(10)(12)(13)(14). Another interesting aspect of zinc status is found in elderly individuals, who in general show a significant reduction of their plasma or serum zinc levels.…”

Section: Discussionmentioning

confidence: 99%

“…The production of proinflammatory cytokines by monocytes is antagonized by an inhibition of phosphodiesterases by zinc (12). Accordingly, zinc can suppress proinflammatory cytokine release during sepsis in in vivo models, but on the other hand, it can also worsen the symptoms (13,14). While low doses of zinc reduce the risk for prostate cancer, higher dosage enhances the incidence (15).…”

Section: Introductionmentioning

confidence: 99%

Differential Gene Expression after Zinc Supplementation and Deprivation in Human Leukocyte Subsets

Haase

Mazzatti

White

et al. 2007

Mol Med

View full text Add to dashboard Cite

“…This is best demonstrated by the effects of zinc administration during septic shock. Within a narrow concentration range, zinc exerts protective effects in endotoxin-challenged mice (48). Although pretreatment with zinc protects against mortality, simultaneous administration of zinc and LPS increases TNF-␣ serum levels, resulting in severe proinflammatory action of zinc and enhanced mortality (48 -50).…”

Section: Discussionmentioning

confidence: 99%

Zinc-Mediated Inhibition of Cyclic Nucleotide Phosphodiesterase Activity and Expression Suppresses TNF-α and IL-1β Production in Monocytes by Elevation of Guanosine 3′,5′-Cyclic Monophosphate

Bülow

Rink

Haase

2005

The Journal of Immunology

143

110

View full text Add to dashboard Cite

The trace element zinc affects several aspects of immune function, such as the release of proinflammatory cytokines from monocytes. We investigated the role of cyclic nucleotide signaling in zinc inhibition of LPS-induced TNF-α and IL-1β release from primary human monocytes and the monocytic cell line Mono Mac1. Zinc reversibly inhibited enzyme activity of phosphodiesterase-1 (PDE-1), PDE-3, and PDE-4 in cellular lysate. It additionally reduced mRNA expression of PDE-1C, PDE-4A, and PDE-4B in intact cells. Although these PDE can also hydrolyze cAMP, only the cellular level of cGMP was increased after incubation with zinc, whereas cAMP was found to be even slightly reduced due to inhibition of its synthesis. To investigate whether an increase in cGMP alone is sufficient to inhibit cytokine release, the cGMP analogues 8-bromo-cGMP and dibutyryl cGMP as well as the NO donor S-nitrosocysteine were used. All three treatments inhibited TNF-α and IL-1β release after stimulation with LPS. Inhibition of soluble guanylate cyclase-mediated cGMP synthesis with LY83583 reversed the inhibitory effect of zinc on LPS-induced cytokine release. In conclusion, inhibition of PDE by zinc abrogates the LPS-induced release of TNF-α and IL-1β by increasing intracellular cGMP levels.

show abstract

Inhibition of Lethality in Endotoxin Challenged Mice Treated With Zinc Chloride

Cited by 22 publications

References 7 publications

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

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

Differential Gene Expression after Zinc Supplementation and Deprivation in Human Leukocyte Subsets

Zinc-Mediated Inhibition of Cyclic Nucleotide Phosphodiesterase Activity and Expression Suppresses TNF-α and IL-1β Production in Monocytes by Elevation of Guanosine 3′,5′-Cyclic Monophosphate

Contact Info

Product

Resources

About