Showing papers by "Lothar Rink published in 2008"
TL;DR: It is demonstrated that 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, and 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+.
Abstract: 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 (Zn(2+)), but this still awaits experimental verification. Zn(2+) 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-alpha. Here we demonstrate that these effects are due to a physiological signaling system involving intracellular Zn(2+) 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-kappaB, and abrogates the release of proinflammatory cytokines, including TNF-alpha. This function of Zn(2+) 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 Ca(2+).
252 citations
TL;DR: This review aims to summarize the respective findings and to discuss possible molecular mechanisms by which zinc could influence viral, bacterial, and parasitic infections, autoimmune diseases, and the response to vaccination.
Abstract: Zinc is required for multiple cellular tasks, and especially the immune system depends on a sufficient availability of this essential trace element. During the last decades, many studies attempted to affect the outcome of various diseases by zinc supplementation. These efforts either aimed at supporting immunity by zinc administration or at correcting a loss of zinc secondary to the disease to restore the zinc-dependent functions of the immune system. This review aims to summarize the respective findings and to discuss possible molecular mechanisms by which zinc could influence viral, bacterial, and parasitic infections, autoimmune diseases, and the response to vaccination. Zinc supplementation in diseases such as diarrhea, chronic hepatitis C, shigellosis, leprosy, tuberculosis, pneumonia, acute lower respiratory infection, and leishmaniasis seems beneficial. In contrast, the results for the common cold and malaria are still not conclusive, and zinc was ineffective in most vaccination and rheumatoid arthritis studies. For AIDS and type 1 diabetes, zinc supplementation may even be a risk factor for increased mortality or deterioration of the glucose metabolism, respectively. In these cases, zinc supplementation should be used with care and limited to clearly zinc-deficient individuals.
193 citations
TL;DR: A review of studies published in which the effect of nutritional zinc supplementation on the incidence or severity of a certain disease was investigated concludes that zinc deficiency may severely affect human health.
178 citations
TL;DR: In this article, the expression of all characterized human zinc exporters (hZnT-1-9) in different leukocyte subsets in response to zinc supplementation and depletion and analyzed their influence on alterations in the intracellular zinc concentration.
Abstract: Intracellular zinc homeostasis is strictly regulated by zinc binding proteins and zinc transporters. In the present study, we quantified in a first global view the expression of all characterized human zinc exporters (hZnT-1-9) in different leukocyte subsets in response to zinc supplementation and depletion and analyzed their influence on alterations in the intracellular zinc concentration. We found that hZnT-1 is the most regulated zinc exporter. Furthermore, we discovered that hZnT-4 is localized in the plasma membrane similar to hZnT-1. hZnT-4 is most highly expressed in Molt-4, up-regulated after treatment with PHA and is responsible for the measured decrease of intracellular zinc content after high zinc exposure. In addition, we found that hZnT-5, hZnT-6, and hZnT-7 in Raji as well as hZnT-6 and hZnT-7 in THP-1 are up-regulated in response to cellular zinc depletion. Those zinc exporters are all localized in the Golgi network, and this type of regulation explains the observed zinc increase in both cell types after up-regulation of their expression during zinc deficiency and, subsequently, high zinc exposure. Furthermore, we detected, for the first time, the expression of hZnT-8 in peripheral blood lymphocytes, which varied strongly between individuals. While hZnT-2 was not detectable, hZnT-3 and hZnT-9 were expressed at low levels. Further on, the amount of expression was higher in primary cells than in cell lines. These data provide insight into the regulation of intracellular zinc homeostasis in cells of the immune system and may explain the variable effects of zinc deficiency on different leukocyte subsets.
113 citations
TL;DR: The experiments show that adjustment of labile zinc by moderate zinc supplementation reduces spontaneous cytokine release and defects in termination of inflammatory activity, which results in reduced amounts of unspecific preactivated T cells and leads to improved T cell response upon mitogenic stimulation.
Abstract: Aging is associated with low-grade inflammation on the one hand and mild zinc deficiency on the other. These conditions contribute to decreased immune functions, resulting in increased incidences of infections and autoimmune diseases. The aim of this study was to give more insight into the question, to what extent is low-grade inflammation caused by zinc deficient status. Here we report the effect of improved intracellular zinc status on low-grade inflammatory activity in 19 healthy elderly subjects. Our experiments show that adjustment of labile zinc by moderate zinc supplementation reduces spontaneous cytokine release and defects in termination of inflammatory activity. This results in reduced amounts of unspecific preactivated T cells and leads to improved T cell response upon mitogenic stimulation. Therefore, in contrast to other anti-inflammatory drugs, zinc does not suppress, but improves immune reaction upon pathogen invasion. These results suggest that mildly zinc-deficient, healthy elderly subjects might benefit from moderate zinc supplementation due to a more balanced immune response with reduced incidences of infections and autoimmune diseases.
104 citations
TL;DR: It is found that women showed higher eSOD activity and lower plasma Zn compared to men, and the potential beneficial effects of Zn supplementation on Zn-dependent antioxidant enzymes in healthy elderly subjects are suggested.
82 citations
TL;DR: An interactive effect of polymorphic alleles of MT1a and IL-6 genes on zinc, IL- 6, MCP-1 and NK activity was evidenced following supplementation, indicating the genetic background as one of the determinants for identifying groups of subjects that can take advantage of therapeutic intervention.
75 citations
TL;DR: Olderly subjects suffer from increased levels of activated T cells and a TH1/TH2 imbalance, and changes in TH2/TH1 subsets are more obvious in women than in men, and advanced healthy aging is accompanied by TH cell polarization, too.
72 citations
TL;DR: The sole assessment of plasma Zn level is not reliable to exclude C- carriers from Zn supplementation, and a possible explanation for the conflicting data on the identification of IL-6-174G as a "risk allele" based on different dietary intake in the studied population is suggested.
64 citations
TL;DR: It is found that there is an IL-2 signalling defect with aging up to 90 years of age which cannot be modulated by zinc and zinc supplementation improved the susceptibility of T cells to AICD in both age-groups, with more efficiency in later ages.
40 citations
TL;DR: The Mediterranean diet score is useful in assessing nutritional influence on immune status in old subjects and there were significant effects of the components of the Mediterranean diet on inflammation markers.
Abstract: BACKGROUND: Aging is associated with low-grade elevation of circulating inflammatory markers, leading to increased risk of morbidity and mortality. The Mediterranean diet has been suggested as a determinant of longevity. In the current study, we investigated the impact of the Mediterranean diet on inflammatory status in old subjects. METHODS: Within the ZINCAGE study, 957 healthy old subjects (>or=60 years old) from five European countries were recruited. Plasma interleukin (IL)-6, IL-8, monocyte chemoattractant protein, tumor necrosis factor-alpha, high-density lipoprotein cholesterol (HDL-C) and erythrocyte sedimentation rate (ESR) were measured. Dietary data were collected applying a food frequency questionnaire and were used to estimate adherence to the Mediterranean diet. RESULTS: The Italians presented the greatest adherence to the Mediterranean diet, while the Polish the poorest. In females, higher diet score was significantly associated with lower body mass index and ESR and higher HDL-C levels (beta=-0.127, p=0.003; beta=-0.144, p=0.001; beta=0.144, p=0.029, respectively). In males, diet score was negatively associated with IL-8 levels (beta=-0.101, p=0.044). The Mediterranean diet was associated with reduced IL-8 concentrations in Greeks (beta=-0.213, p=0.007). CONCLUSIONS: There were significant effects of the components of the Mediterranean diet on inflammation markers. The Mediterranean diet score is useful in assessing nutritional influence on immune status.
TL;DR: It is reported that metallothionein protein levels also decrease in very old age, and that this is independent of dietary zinc intake, suggesting that phenomena observed invery old people can be at least partially attributed to diminished cell proliferation.
Abstract: It is known that metallothionein (MT) mRNA expression first increases with age, but then decreases again in the very elderly. Here we report that MT protein levels also decrease in very old age, and that this is independent of dietary zinc intake. Age-related changes of MT, as well as alterations of zinc homeostasis (intracellular labile zinc and NO-induced zinc release), occur both in human PBMCs ex vivo and also in CD4+ T cell clones progressing through their finite life span in vitro. These results suggest that phenomena observed in very old people can be at least partially attributed to diminished cell proliferation.
TL;DR: The results show that the region‐specific DC have a unique phenotype and an impact on the ratio of CD4 : CD8 T cells during an immune response in vivo.
Abstract: Dendritic cells (DC) are important in differential T-cell priming. Little is known about the local priming by DC in the microenvironment of different lymph nodes and about the fate of the imprinted T cells. Therefore, freshly isolated rat DC from mesenteric lymph nodes (mLN) and axillary lymph nodes (axLN) were phenotyped and cultured with blood T cells in the presence of the superantigen Mycoplasma arthritidis mitogen (MAM). The phenotype, proliferation and apoptosis of the primed T cells were analysed. Our data show that a common DC population exists in both mLN and axLN. In addition, region-specific DC with an organotypical marker expression imprinted by the drained area were found. Coculture of T cells with DC from mLN or axLN resulted in a distinct shift in the CD4 and CD8 expression of T cells and their phenotype. Furthermore, when these differentially primed mLN and axLN T cells were injected into recipients, mLN-primed T cells survived longer in other lymphoid organs. The results show that the region-specific DC have a unique phenotype and an impact on the ratio of CD4 : CD8 T cells during an immune response in vivo.
TL;DR: Microarray technology was used to assess the effects of zinc supplementation and depletion on global gene expression, and functional networks were analyzed, showing that the well known effect of zinc on pro-inflammatory cytokines is not limited to these genes; it acts on a number of functionally connected genes, as well.
TL;DR: The choice of old subjects for zinc supplementation is discussed in relation to their genetic background of MT and IL-6, because both affect intracellular zinc homeostasis.
Abstract: Aging is characterized by spontaneous biochemical changes that may predispose to increased susceptibility to diseases. Zinc may remodel these changes leading to healthy aging because zinc ...