Showing papers by "Lothar Rink published in 2006"

Correlation between zinc status and immune function in the elderly

Abstract: Zinc is essential for the immune system and elderly people have an increased probability for zinc deficiency, documented by a decline of serum or plasma zinc levels with age. Although most healthy elderly are not classified as clinically zinc deficient, even marginal zinc deprivation can affect immune function. Several striking similarities in the immunological changes during aging and zinc deficiency, including a reduction in the activity of the thymus and thymic hormones, a shift of the T helper cell balance towards TH2, decreased response to vaccination, and impaired functions of innae immune cells indicate that a wide prevalence of marginal zinc deficiency in elderly people may contribute to immunosenescence. Studies with oral zinc supplementation show the potential to improve the immune response of elderly people by restoration of the zinc levels, showing that balancing the zinc status may be a way to healthy aging. This review summarizes the current literature about zinc supplementation in the elderly and thereby defines the rationale for the immunological part of the ZINCAGE project.

Zinc status, psychological and nutritional assessment in old people recruited in five European countries: Zincage study.

Abstract: The paper shows the results on the relationship between zinc status, psychological dimensions (cognitive functions, mood, perceived stress) and nutritional aspects in European healthy old subjects recruited for ZINCAGE Project (supported by the European Commission in the Sixth Framework Programme). The old healthy subjects were recruited in Italy, Greece, Germany, France, Poland taking into account the different dietary habits between Northern and Southern European Countries and the pivotal role played by zinc for psychological functions. Measures of the cognitive status, mood and perceived stress level were obtained at baseline, using the “Mini Mental State Examination (MMSE)”; the “Geriatric Depression Scale (GDS – 15 items)” and the “Perceived Stress Scale (PSS)”, respectively. Nutritional status was assessed using “Frequency Food Questionnaire”. The sample included 853 old subjects, classified in 4 groups of age: 60–69-years-old (n = 359); 70–74-years-old (n = 225); 75–79-years-old (n = 153); 80–84-years-old (n = 116). Subjects were studied on the basis of plasma zinc, in which zinc ≤11 μM means marginal zinc deficiency. The total samples showed that the 82% had no cognitive decline, whereas 76% presented a low GDS value indicating no depression. However, all psychological variables were related to plasma zinc values and nutritional assessment. In particular, a relationship between marginal zinc deficiency and impaired psychological dimensions occurred in Greece than in other European countries due to low intake and less variety of foods rich of zinc. This phenomenon was independent by the age, suggesting that a correct zinc intake from a wide range of foods may be useful to maintain a satisfactory plasma zinc levels as well as psychological status in elderly with subsequent achievement of healthy ageing.

Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators.

Abstract: The role of neutrophils in the immune response has long been regarded as mainly phagocytic, but recent publications have indicated the production of several cytokines by polymorphonuclear leucocytes (PMN). The results of the individual reports, however, vary considerably. In this study, we established a cytokine profile of pure human neutrophils and demonstrated that minor contamination of peripheral blood mononuclear cells (PBMCs) in PMN preparations can lead to false-positive results. In our hands, peripheral blood PMN fail to produce the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha). Instead, they secrete large amounts of the chemokine IL-8 and the anti-inflammatory IL-1 receptor antagonist (IL-1ra). Additionally, PMN preparations of a high purity show production of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and growth-related oncogene-alpha (GRO-alpha), as well as macrophage colony-stimulating factor (M-CSF). The neutrophil therefore represents a novelty by producing the antagonist of IL-1beta (i.e. IL-1ra) in the absence of IL-1beta itself. To support our results, we differentiated stem cells from human cord blood into PMN and monocytes, respectively. These in vitro-differentiated PMN showed the same cytokine profile as peripheral blood PMN lacking IL-1beta, while differentiated monocytes produced the expected IL-1beta in addition to IL-1ra. The clear anti-inflammatory nature of their cytokine profile enables PMN to antagonize pro-inflammatory signals in experimental conditions. It is therefore possible that PMN play a key role in immune regulation by counteracting a dysregulation of the inflammatory process. Clinical studies, in which administration of recombinant G-CSF had a favourable effect on the outcome of severe infections and even sepsis without worsening inflammation, could thus be explained by our results.

Effect of improved zinc status on T helper cell activation and TH1/TH2 ratio in healthy elderly individuals

Abstract: Mild zinc deficiency is a common condition in healthy elderly individuals leading to impaired cell-mediated immune response. Here we report the effect of improved zinc status on TH1/TH2 balance and on the activation status of T helper cells in 19 healthy elderly subjects aged 69.8 ± 5.1 years. Our investigations revealed a mild zinc deficiency which was adjusted by oral zinc supplementation for seven weeks. Improved serum zinc levels significantly reduced levels of activated T helper cells whereas changes in TH1/TH2 ratio (determined by CCR4 and CCR5 expression) were not observed. These findings suggest that elderly individuals may benefit from moderate zinc supplementation due to improved immune response leading to reduced incidences of autoimmune diseases and infections.

β-(1→3)-D-glucan modulates DNA binding of nuclear factors κB, AT and IL-6 leading to an anti-inflammatory shift of the IL-1β/IL-1 receptor antagonist ratio

Abstract: β-1→3-D-glucans represent a pathogen-associated molecular pattern and are able to modify biological responses. Employing a comprehensive methodological approach, the aim of our in vitro study was to elucidate novel molecular and cellular mechanisms of human peripheral blood immune cells mediated by a fungal β-1→3-D-glucan, i.e. glucan phosphate, in the presence of lipopolysaccharide (LPS) or toxic shock syndrome toxin 1 (TSST-1). Despite an activation of nuclear factor (NF)κB, NFinterleukin(IL)-6 and NFAT similar to LPS or TSST-1, we observed no significant production of IL-1β, IL-6, tumor necrosis factor α or interferon γ induced by glucan phosphate. Glucan phosphate-treated leukocytes induced a substantial amount of IL-8 (peak at 18 h: 5000 pg/ml), likely due to binding of NFκB to a consensus site in the IL-8 promoter. An increase in IL-1receptor antagonist(RA) production (peak at 24 h: 12000 pg/ml) by glucan phosphate-treated cells positively correlated with IL-8 levels. Glucan phosphate induced significant binding to a known NFIL-6 site and a new NFAT site within the IL-1RA promoter, which was confirmed by inhibition experiments. When applied in combination with either LPS or TSST-1 at the same time points, we detected that glucan phosphate elevated the LPS- and the TSST-1-induced DNA binding of NFκB, NFIL-6 and NFAT, leading to a synergistic increase of IL-1RA. Further, glucan phosphate modulated the TSST-1-induced inflammatory response via reduction of IL-1β and IL-6. As a consequence, glucan phosphate shifted the TSST-1-induced IL-1β/IL-1RA ratio towards an anti-inflammatory phenotype. Subsequently, glucan phosphate decreased the TSST-1-induced, IL-1-dependent production of IL-2. Thus, β-1→3-D-glucans may induce beneficial effects in the presence of pro-inflammatory responses, downstream of receptor binding and signaling by switching a pro- to an anti-inflammatory IL-1RA-mediated reaction. Our results also offer new insights into the complex regulation of the IL-1RA gene, which can be modulated by a β-1→3-D-glucan.

Zinc homeostasis in aging: two elusive faces of the same "metal".

Abstract: Proteins involved in zinc homeostasis may be altered in aging. This phenomenon may lead to zinc deficiency in the peripheral blood and an accumulation of zinc bound to insoluble aggregates at the extracellular level in the brain. Therefore, it should be more correct to talk about aging as a condition associated with zinc dyshomeostasis rather than deficiency. Restoring functional zinc homeostasis in aging people is an attractive field for antiaging research, but requires further knowledge than the current state of the art.

Zinc and ageing (ZINCAGE Project)

Abstract: research project (STREP) funded by the European Union in the 6th Framework Program (FP6). It involves epidemiological studies on the influence of diet and lifestyle on healthy ageing, aimed at preventing adult degenerative disease, particularly focusing on atherosclerosis and also addressing malnutrition of the elderly. The 3rd ZincAge meeting, held in Madrid (February 11–13, 2006) at CNIO Institute, brought together biochemical, genetic and lifestyle implications for healthy ageing in the context of nutritional impact of zinc. It is quite clear that antioxidant and micronutrients in the diet, such as zinc, influence the development and function of immune cells, the activity of stress-related proteins and antioxidant enzymes and help to maintain genomic integrity and stability. All these functions occur through the action of proteins involved in the regulation of zinc homeostasis, such as Metallothioneins (MT), which bind zinc with high affinity but, at the same time, release free zinc ions in response to oxidative/nitrosative stress to modulate the expression of zinc-dependent genes and to activate antioxidant enzymes and impact immune response. Thus, the role of zinc is mainly to transduce oxidative stress and other signals converging at the production of nitric oxide into a specific intracellular response, suggesting an intriguing task of ‘‘signal transducer’’, similar to that found for calcium in the past. However, many aspects of this model are still unexplored, because the intracellular mechanisms involved in the regulation zinc homeostasis have been poorly studied in ageing. It is known that during ageing, the intake of zinc decreases, thus contributing to cause frailty, general disability and increased incidence of agerelated degenerative diseases (cancer, infections and atherosclerosis). This situation may be better or worse in different European countries, taking into account the large differences in dietary habits between southern and northern areas. One of the aim of the ZincAge project is therefore to investigate how different dietary habits and intrinsic factors (genetic background) contribute to the Presented at the ZincAge Conference, Madrid, February 10-13, 2006.

The superantigen-induced polarization of T cells in rat peripheral lymph nodes is influenced by genetic polymorphisms in the IL-4 and IL-6 gene clusters.

Abstract: In recent years, it has become clear that the polarization of T cells depends on the genetic background. However, due to the complexity of the genetic background of each animal, a direct comparison of the phenotype is difficult. In this study, a new rat strain LEW.BN-4-10 carrying the chromosomal regions on chromosomes 4 and 10, which harbor IL-6 and IL-4 gene clusters of BN, has been bred on the genetic background of LEW. It was asked whether these two gene clusters influence the polarization of T cell responses. As a model, the Mycoplasma arthritidis mitogen (MAM)-induced inflammation was used focusing on the microenvironment of the draining lymph node (LN). The effect of differences in these regions was tested by comparing LEW.BN-4-10 and LEW rats under steady-state conditions and upon injection of MAM into the forepaw. Under steady-state conditions, the two strains showed differences in the dendritic cell (DC) subset composition. When MAM was injected, the number of T cells in LEW.BN-4-10 rats producing T(h)2 cytokines such as IL-4 and IL-13 was significantly increased compared with LEW. The data suggest that these differences in the microenvironments in LN of LEW and LEW.BN-4-10 rats resulted in different susceptibility to the disease (increase of cells in LN and paw swelling). In addition, deviations in the distribution and function of injected effector T cells were found in the LN of LEW and LEW.BN-4-10 rats after MAM treatment. The data indicate that the IL-6 and IL-4 gene clusters are involved in polarizing T cell responses in vivo.