Update on the multi-layered levels of zinc-mediated immune regulation.

The significance of zinc for an efficient immune response is well accepted. During zinc deficiency, an increase in the myeloid to lymphoid immune cells ratio was observed. This results in a disturbed balance of pro- and anti-inflammatory processes as well as defects in tolerance during infections. Consequently, instead of efficiently defending the body against invading pathogens, damage of host cells is frequently observed. This explains the increased susceptibility to infections and their severe progression observed for zinc deficient individuals as well as the association of autoimmune diseases with low serum zinc levels. Together with the advances in techniques for investigating cellular development, communication and intracellular metabolism, our understanding of the mechanisms underlying the benefits of zinc for human health and the detriments of zinc deficiency has much improved. As analyses of the zinc status and effects of zinc supplementation were more frequently included into clinical studies, our knowledge of the association of zinc deficiency to a variety of diseases was strongly improved. Still there are several areas in zinc biology that require further in-depth investigation such as the interaction with other nutritional elements, the direct association between zinc transportation, membrane-structure, receptors, and signaling as well as its role in cell degeneration. This article will describe our current understanding of the role of zinc during the immune response focusing on the most recent findings and underlying mechanisms. Research questions that need to be addressed in the future will be discussed as well.

Intensity- and time-matched acute interval and continuous endurance exercise similarly induce an anti-inflammatory environment in recreationally active runners: focus on PD-1 expression in Tregs and the IL-6/IL-10 axis.

PURPOSE: Acute exercise elicits a transient anti-inflammatory state during the early recovery period. Since recent studies reported on regimen-specific effects on immune-related humoral factors and cellular subsets, this study compared the effects of intensity- and time-matched acute interval and continuous exercise on peripheral anti-inflammatory cellular and humoral immune parameters with a particular focus on the PD-1 expression in CD4+ regulatory T cells (Tregs). METHODS: Twenty-four recreationally active runners (age: 29.7 ± 4.3 years, BMI: 22.2 ± 2.4, VO2peak: 56.6 ± 6.4 ml × kg-1 × min-1) participated in this crossover RCT. Each subject conducted a moderate continuous (MCE) and a high-intensity interval exercise (HIIE) session in a counterbalanced design. Blood was drawn before, immediately after, and 1 h after exercise. Treg subsets and levels of PD-1 and Foxp3 were assessed by flow cytometry. Serum levels of IL-10 and IL-6 were quantified by ELISA. RESULTS: PD-1 levels on Tregs increased within the recovery period after HIIE (p < .001) and MCE (p <  0.001). Total counts of Tregs (HIIE: p = 0.044; MCE: p = .021), naïve Tregs (HIIE: p  < 0.001; MCE: p  < 0.001), and PD-1+ effector Tregs (eTregs) (HIIE: p = .002) decreased 1 h after exercise. IL-10 increased 1 h after HIIE (p < 0.001) and MCE (p = 0.018), while IL-6 increased immediately after both HIIE (p = 0.031) and MCE (p = 0.021). Correlations between changes in IL-6 and IL-10 (p = 0.017, r = 0.379) and baseline VO2peak and Treg frequency (p = 0.002, r = 0.660) were identified. CONCLUSION: This is the first study that investigates PD-1 expression in circulating Tregs after acute exercise, revealing an increase in PD-1 levels on eTregs during the early recovery period after intensity- and time-matched HIIE and MCE. Future studies are needed to investigate the PD-1 signalosome in eTregs, together with the expression of key effector molecules (i.e., IL-10, TGF-ß, IL-35, CTLA-4) to elucidate PD-1-dependent changes in cellular function. Based on changes in serum cytokines, this study further reveals a regimen-independent establishment of an anti-inflammatory milieu and underpins the role of the IL-6/IL-10 axis.

Dietary and Physiological Effects of Zinc on the Immune System.

Evidence for the importance of zinc for all immune cells and for mounting an efficient and balanced immune response to various environmental stressors has been accumulating in recent years. This article describes the role of zinc in fundamental biological processes and summarizes our current knowledge of zinc's effect on hematopoiesis, including differentiation into immune cell subtypes. In addition, the important role of zinc during activation and function of immune cells is detailed and associated with the specific immune responses to bacteria, parasites, and viruses. The association of zinc with autoimmune reactions and cancers as diseases with increased or decreased immune responses is also discussed. This article provides a broad overview of the manifold roles that zinc, or its deficiency, plays in physiology and during various diseases. Consequently, we discuss why zinc supplementation should be considered, especially for people at risk of deficiency.

Zinc deficiency as a possible risk factor for increased susceptibility and severe progression of Corona Virus Disease 19.

The importance of Zn for human health becomes obvious during Zn deficiency. Even mild insufficiencies of Zn cause alterations in haematopoiesis and immune functions, resulting in a proinflammatory phenotype and a disturbed redox metabolism. Although immune system malfunction has the most obvious effect, the functions of several tissue cell types are disturbed if Zn supply is limiting. Adhesion molecules and tight junction proteins decrease, while cell death increases, generating barrier dysfunction and possibly organ failure. Taken together, Zn deficiency both weakens the resistance of the human body towards pathogens and at the same time increases the danger of an overactive immune response that may cause tissue damage. The case numbers of Corona Virus Disease 19 (COVID-19) are still increasing, which is causing enormous problems for health systems and economies. There is an urgent need to reduce both the number of severe cases and the resulting deaths. While therapeutic options are still under investigation, and first vaccines have been approved, cost-effective ways to reduce the likelihood of or even prevent infection, and the transition from mild symptoms to more serious detrimental disease, are highly desirable. Nutritional supplementation might be an effective option to achieve these aims. In this review, we discuss known Zn deficiency effects in the context of an infection with Severe Acute Respiratory Syndrome-Coronavirus-2 and its currently known pathogenic mechanisms and elaborate on how severe pre-existing Zn deficiency may pre-dispose patients to a severe progression of COVID-19. First published clinical data on the association of Zn homoeostasis with COVID-19 and registered studies in progress are listed.

Short-term zinc supplementation of zinc-deficient seniors counteracts CREMα - mediated IL-2 suppression.

BACKGROUND: Aging is accompanied by a dramatic decline in the interleukin (IL)-2 production capacity of human immune cells, thus making seniors more susceptible to a variety of age-related diseases. A common cause of impaired cytokine production in advanced age is a deficiency of the essential micronutrient zinc. Nevertheless, the molecular mechanisms underlying a zinc deficiency-induced decrease in IL-2 production have not yet been satisfactorily elucidated. Recent animal and in vitro data suggested that the transcription factor cAMP-responsive element modulator (CREM) [Formula: see text] plays a critical role in T cells´ disturbed IL-2 production in suboptimal zinc conditions. However, its role in the human aging process and the possibility of influencing this detrimental process by short-term zinc supplementation have not yet been evaluated. RESULTS: Comparing peripheral lymphocytes of 23 young and 31 elderly subjects with either high, intermediate, or deficient zinc status, we observed zinc-dependent regulation of the IL-2 production mediated by the transcription factor CREM [Formula: see text]. For the first time in humans, we report a mutual relationship between low zinc levels, high CREM [Formula: see text] expression, subsequent impaired IL-2 production, and vice versa. Remarkably, an average of only 6 days of in vivo zinc supplementation to zinc-deficient seniors was sufficient to rapidly improve zinc status, reverse CREM [Formula: see text] overexpression, and counteract subsequent low IL-2 production rates. CONCLUSIONS: Our ex vivo and in vivo data identify zinc deficiency-mediated CREM [Formula: see text] overexpression as a key cellular mechanism underlying impaired IL-2 production in the elderly and point toward the use of zinc as a rapidly immune-enhancing add-on nutraceutical in geriatric therapy. During the aging process, there is a progressive decrease in zinc status, which in turn leads to overexpression of the transcription factor CREM[Formula: see text] in peripheral lymphocytes. CREMα is a negative regulator of the IL-2 gene, the overexpression of which dramatically limits adequate IL-2 production. This deleterious mechanism can be counteracted by short-term oral zinc administration, which can adjust IL-2 production in old, zinc-deficient individuals to a level similar to that of young adults.

Zinc Status Impacts the Epidermal Growth Factor Receptor and Downstream Protein Expression in A549 Cells.

Zinc has been suggested to play a role in carcinogenesis and tumor progression. Serum zinc levels of lung cancer patients are for example lower than in healthy individuals. The activation and expression of the epidermal growth factor receptor (EGFR), which plays a role in tumor biology, are presumably influenced by zinc. EGFR activation influences cell adhesion and immune escape. This study provides insights into the impacts of zinc on the EGFR activation and expression of downstream proteins such as E-cadherin and PD-L1 in the alveolar carcinoma cell line A549. To model chronic changes in zinc homeostasis, A549 cells were cultured in media with different zinc contents. EGFR surface expression of unstimulated and stimulated A549 cells was determined by flow cytometry. EGFR phosphorylation as well as the protein expression of E-cadherin and PD-L1 were analyzed by Western blot. In our hands, chronic zinc deficiency led to increased EGFR surface expression, decreased E-cadherin protein expression and increased PD-L1 protein expression. Zinc supplementation decreased EGFR surface expression and PD-L1 protein expression. In summary, zinc-deficient A549 cells may display a more malignant phenotype. Thus, future clinical research should further focus on the possible benefits of restoring disturbed zinc homeostasis, especially in lung cancer patients.

Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity.

INTRODUCTION: Zinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury (ALI). As deregulated neutrophil recruitment and their hyper-activation are hallmarks of ALI, benefits of zinc supplementation on the development of lipopolysaccharides (LPS)-induced ALI were tested. METHODS: 64 C57Bl/6 mice, split into eight groups, were injected with 30 µg zinc 24 hours before exposure to aerosolised LPS for 4 hours. Zinc homoeostasis was characterised measuring serum and lung zinc concentrations as well as metallothionein-1 expression. Recruitment of neutrophils to alveolar, interstitial and intravascular space was assessed using flow cytometry. To determine the extent of lung damage, permeability and histological changes and the influx of protein into the bronchoalveolar lavage fluid were measured. Inflammatory status and PMN activity were evaluated via tumour necrosis factor α levels and formation of neutrophil extracellular traps. The effects of zinc supplementation prior to LPS stimulation on activation of primary human granulocytes and integrity of human lung cell monolayers were assessed as well. RESULTS: Injecting zinc 24 hours prior to LPS-induced ALI indeed significantly decreased the recruitment of neutrophils to the lungs and prevented their hyperactivity and thus lung damage was decreased. Results from in vitro investigations using human cells suggest the transferability of the finding to human disease, which remains to be tested in more detail. CONCLUSION: Zinc supplementation attenuated LPS-induced lung injury in a murine ALI model. Thus, the usage of zinc-based strategies should be considered to prevent detrimental consequences of respiratory infection and lung damage in risk groups.

Increase of the Intracellular Zinc Concentration Leads to an Activation and Internalisation of the Epidermal Growth Factor Receptor in A549 Cells.

(1) Background: Zinc is suggested to play a major role in epidermal growth factor (EGF)-induced cell regeneration and proliferation. To deepen the knowledge on the underlying mechanisms zinc's effects on the epidermal growth factor receptor (EGFR) activation and its endocytosis was investigated in the alveolar carcinoma cell line A549. (2) Methods: An increase of intracellular zinc was generated by adding zinc extracellularly compared to the intracellular release of zinc from zinc-binding proteins by stimulation with a nitric oxide donor. Zinc-initiated EGFR phosphorylation was checked by Western blotting and receptor endocytosis assays were performed by using flow cytometry. (3) Results: Besides a dose-dependent EGFR phosphorylation, a dose- and time dependent significant receptor internalisation was initiated by both types of zinc increases. In addition, both increased intracellular zinc levels further promoted EGF-induced EGFR phosphorylation and internalisation. (4) Conclusion: This report confirms a transactivating effect of zinc on the EGFR for A549 cells and is the first describing an influence of zinc on the EGFR endocytosis. The transferability of the fine-tuning of EGFR-induced signalling by zinc needs to be verified in vivo, but the presented data underline that zinc might be helpful during treatment of disturbed regeneration and tissue repair.

Zinc Signals and Immunity.

Zinc homeostasis is crucial for an adequate function of the immune system. Zinc deficiency as well as zinc excess result in severe disturbances in immune cell numbers and activities, which can result in increased susceptibility to infections and development of especially inflammatory diseases. This review focuses on the role of zinc in regulating intracellular signaling pathways in innate as well as adaptive immune cells. Main underlying molecular mechanisms and targets affected by altered zinc homeostasis, including kinases, caspases, phosphatases, and phosphodiesterases, will be highlighted in this article. In addition, the interplay of zinc homeostasis and the redox metabolism in affecting intracellular signaling will be emphasized. Key signaling pathways will be described in detail for the different cell types of the immune system. In this, effects of fast zinc flux, taking place within a few seconds to minutes will be distinguish from slower types of zinc signals, also designated as "zinc waves", and late homeostatic zinc signals regarding prolonged changes in intracellular zinc.

Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation.

Integrity of the immune system is particularly dependent on the availability of zinc. Recent data suggest that zinc is involved in the development of sepsis, a life-threatening systemic inflammation with high death rates, but with limited therapeutic options. Altered cell zinc transport mechanisms could contribute to the inflammatory effects of sepsis. Zip14, a zinc importer induced by proinflammatory stimuli, could influence zinc metabolism during sepsis and serve as a target for therapy. Using cecal ligation-and-puncture (CLP) to model polymicrobial sepsis, we narrowed the function of ZIP14 to regulation of zinc homeostasis in hepatocytes, while hepatic leukocytes were mostly responsible for driving inflammation, as shown by higher expression of IL-1ß, TNFα, S100A8, and matrix metalloproteinase-8. Using Zip14 knockout (KO) mice as a novel approach, we found that ablation of Zip14 produced a delay in development of leukocytosis, prevented zinc accumulation in the liver, altered the kinetics of hypozincemia, and drastically increased serum IL-6, TNFα, and IL-10 concentrations following CLP. Hence, this model revealed that the zinc transporter ZIP14 is a component of the pathway for zinc redistribution that contributes to zinc dyshomeostasis during polymicrobial sepsis. In contrast, using the identical CLP model, we found that supplemental dietary zinc reduced the severity of sepsis, as shown by amelioration of cytokines, calprotectins, and blood bacterial loads. We conclude that the zinc transporter ZIP14 influences aspects of the pathophysiology of nonlethal polymicrobial murine sepsis induced by CLP through zinc delivery. The results are promising for the use of zinc and its transporters as targets for future sepsis therapy.

A combined biochemical and cellular approach reveals Zn2+-dependent hetero- and homodimeric CD4 and Lck assemblies in T cells.

The CD4 or CD8 co-receptors' interaction with the protein-tyrosine kinase Lck initiates the tyrosine phosphorylation cascade leading to T cell activation. A critical question is: to what extent are co-receptors and Lck coupled? Our contribution concerns Zn2+, indispensable for CD4- and CD8-Lck formation. We combined biochemical and cellular approaches to show that dynamic fluctuations of free Zn2+ in physiological ranges influence Zn(CD4)2 and Zn(CD4)(Lck) species formation and their ratio, although the same Zn(Cys)2(Cys)2 cores. Moreover, we demonstrated that the affinity of Zn2+ to CD4 and CD4-Lck species differs significantly. Increased intracellular free Zn2+ concentration in T cells causes higher CD4 partitioning in the plasma membrane. We additionally found that CD4 palmitoylation decreases the specificity of CD4-Lck formation in the reconstituted membrane model. Our findings help elucidate co-receptor-Lck coupling stoichiometry and demonstrate that intracellular free Zn2+ has a major role in the interplay between CD4 dimers and CD4-Lck assembly.

Leukemia cells accumulate zinc for oncofusion protein stabilization.

Acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML) are both hematological malignancies characterized by genetic alterations leading to the formation of oncofusion proteins. The classical chromosomal aberrations in APL and CML result in the PML-RARα and BCR-ABL1 oncofusion proteins, respectively. Interestingly, our flow cytometric analyses revealed elevated free intracellular zinc levels in various leukemia cells, which may play a role in stabilizing oncofusion proteins in leukemia and thus support cell proliferation and malignancy. Long-term zinc deficiency resulted in the degradation of PML-RARα in NB4 cells (APL cell line) and of BCR-ABL1 in K562 cells (CML cell line). This degradation may be explained by increased caspase 3 activity observed in zinc deficient cells, whereas zinc reconstitution normalized the caspase 3 activity and abolished zinc deficiency-induced oncofusion protein degradation. In NB4 cells, fluorescence microscopic images further indicated enlarged and enriched lysosomes during zinc deficiency, suggesting increased rates of autophagy. Moreover, NB4 cells exhibited increased expression of the zinc transporters ZIP2, ZIP10 and ZnT3 during zinc deficiency and revealed excessive accumulation of zinc in contrast to healthy peripheral blood mononuclear cells (PBMCs), when zinc was abundantly available extracellularly. Our results highlight the importance of altered zinc homeostasis for some characteristics in leukemia cells, uncover potential pathways underlying the effects of zinc deficiency in leukemia cells, and provide potential alternative strategies by which oncofusion proteins can be degraded.

Regulation of matrix metalloproteinase-9 during monopoiesis and zinc deficiency by chromatin remodeling.

INTRODUCTION: Matrix metalloproteinase-9 (MMP-9) cleaves various extracellular matrix proteins, hence significantly contributes to numerous physiological but also pathological processes. Monocytic differentiation is associated with increased MMP-9 gene expression. Interestingly, MMP-9 upregulation during monocytic differentiation is paralleled by a decline in intracellular zinc levels. Hence, an influence of zinc on the regulation of MMP-9 expression may exist. Although, previous studies suggest a vital role of zinc regarding MMP-9 activity, the possible relevance of zinc homeostasis during transcriptional regulation of MMP-9 for example via epigenetic mechanisms is rather unclear. AIM: This study aims to find a correlation between zinc deficiency and MMP-9 transcriptional regulation, focusing on epigenetics as the possible mechanism behind zinc deficiency-induced changes. METHODS: The effect of differentiation and zinc deficiency on MMP-9 expression and MMP9 promoter accessibility was investigated using the acute promyelocytic cell line NB4. Intracellular free zinc levels were detected by flow cytometry. MMP-9 gene expression was measured by real-time PCR and ELISA. Analysis of chromatin structures was done using chromatin accessibility by real-time PCR (CHART) assay. RESULTS: During monocytic differentiation of NB4 cells, the decrease in intracellular zinc levels was paralleled by an increased production of MMP-9. Assessment of chromatin structure revealed increased accessibility of certain regions within the MMP-9 promoter in differentiated cells. Interestingly, upregulated activation-induced MMP-9 gene expression as well as a more accessible MMP-9 promoter were in zinc-deficient NB4 cells whereas zinc resupplementation reversed the effects. CONCLUSION: These data demonstrate an important role of epigenetic mechanisms in regulating MMP-9 expression under zinc deficiency. This could provide an encouraging step to expand the research on using zinc for the treatment of various pathological conditions such as inflammatory, vascular and autoimmune diseases resulting from MMP-9 deregulation.

Effects of Zinc Status on Expression of Zinc Transporters, Redox-Related Enzymes and Insulin-like Growth Factor in Asian Sea Bass Cells.

Since Asian sea bass is one of the economically most important fish, aquaculture conditions are constantly optimized. Evidence from feeding studies combined with the current understanding of the importance of zinc for growth and immune defense suggest that zinc supplementation may be a possible approach to optimize aquacultures of Asian sea bass. To investigate the effects of zinc deficiency and zinc supplementation, cells from Asian sea bass were incubated in culture medium with different zinc contents. The expression of genes, important for zinc homeostasis, redox metabolism, and growth hormones was analyzed using RT-PCR. Zinc deficiency induced the expression of certain zinc transporters (ZIP14, ZIP10, ZIP6, ZIP4, ZnT4, ZnT9) as well as of SOD1, IGF I and IGF II, while expression of ZnT1 and metallothionein (MT) was reduced. Zinc supplementation decreased the expression of ZIP10, while expression of ZnT1 and MT were elevated. No differences in the effects of zinc supplementation with zinc sulfate compared to supplementation with zinc amino acid complexes were observed. Thus, extracellular zinc conditions may govern the cellular zinc homeostasis, the redox metabolism and growth hormone expression in cells from Asian sea bass as reported for other fish species. Our data indicate that supplementing aquacultures with zinc may be recommended to avoid detriments of zinc deficiency.

Zinc supplementation prior to heat shock enhances HSP70 synthesis through HSF1 phosphorylation at serine 326 in human peripheral mononuclear cells.

Zinc supplementation prior to heat shock increases HSP70 (heat shock protein 70) expression, which has cytoprotective effects in tissue cells during inflammation. Effects of zinc deficiency in this regard have been discussed controversially. Whether zinc modulates the expression of HSP70 in the human immune system as well and thus affects cell survival during heat stress is so far largely unknown. Therefore, we investigated the effect of alterations in the cellular zinc status on HSP70 expression and on cellular survival in human monocytes and lymphocytes. Three cell lines (Jurkat, THP-1, and Ramos) and enriched primary human monocytes and lymphocytes from young subjects were subjected to zinc deficiency or supplementation and subsequently heat shock at 42 °C. HSP70 mRNA expression was analyzed by real-time PCR, whereas HSP70 protein expression was analyzed by western blotting. In all cells other than Ramos cells, zinc supplementation and deficiency augmented heat shock-induced HSP70 expression. Further experiments in primary monocytes and lymphocytes indicated that this may be explained by the enhanced phosphorylation of HSF1 (Heat shock factor 1) at Ser326, which plays a significant role in HSP70 induction, as observed in zinc deficient and supplemented cells. While zinc supplementation had negligible effects on cell viability, acute zinc deficiency further increased cell death, induced by heat shock. Our results emphasize the importance of an optimal cellular zinc status. Moreover, we present a possible mechanism behind zinc's influence on HSP70 expression in human leukocytes. Our data form the basis for further in vivo and ex vivo studies to investigate how the zinc status may affect cellular damage in transient high temperature situations.

Vitamin D3 and zinc synergistically induce regulatory T cells and suppress interferon-γ production in mixed lymphocyte culture.

Although vitamin D3 (cholecalciferol) and zinc are known to individually shift the immune response towards tolerance, little is known about the effect of their combined administration. This work contributes to understanding the combined action of zinc and vitamin D3 in different in vitro models for immune reactions. Zinc and vitamin D3 in combination boosted the differentiation into Foxp3+CD4+ T cells (Treg). Vitamin D3 alone reduced the percentage of CD4+T-bet+ T cells (TH1). In mixed lymphocyte culture (MLC), therapeutic concentrations of vitamin D3 and zinc in combination suppressed interferon-γ (IFN-γ) secretion more strongly than the single agent treatment. This effect was also detected for a combination of subtherapeutic concentrations of both vitamin D3 and zinc. Vitamin D3, even at nanomolar concentrations, increased intracellular zinc levels. PBMC (peripheral blood mononuclear cells) of individuals at risk of zinc deficiency responded to vitamin D3 treatment with a higher mRNA expression of Zip13. In PBMC, both agents reduced activation-induced IL-17 secretion. In summary, this study shows, for the first time, a vitamin D3-induced upregulation of CD4+Foxp3+ T cells in MLC. The data propose a model where zinc augments the effect of vitamin D3 in certain therapeutic and subtherapeutic concentrations. Lower concentrations of both vitamin D3 and zinc could be used for effective treatment, thus reducing possible side effects from vitamin D3 and zinc. Vitamin D3 and zinc in combination may be a promising and cheap option to treat dysregulated immune response in various conditions.

Zinc Levels Affect the Metabolic Switch of T Cells by Modulating Glucose Uptake and Insulin Receptor Signaling.

SCOPE: T cell activation requires a metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis to rapidly provide substrates for biosynthesis. An individual's zinc status plays an important role in balancing the activation of T cells and is required for a proper function of immune cells. Furthermore, zinc plays an important role during effector T cell polarization to T helper cell subsets or regulatory T cells, with effector T cells relying on glycolysis and regulatory T cells on oxidative phosphorylation. Therefore, the study aims to analyze if zinc also impacts on T cell activation on the level of intracellular metabolism. METHODS AND RESULTS: Mixed lymphocyte culture and anti-CD3/CD28 stimulation is used as in vitro models for T cell activation to investigate the effect of zinc supplementation and deprivation on metabolic switching. Promoted glucose uptake, insulin receptor expression, and signaling in both zinc conditions are observed, whereas key metabolic enzymes are stimulated mainly by zinc deprivation. Alterations in cytokine production suggest an immune-activating effect of zinc deprivation and a balancing effect of zinc supplementation. CONCLUSION: The results suggest a supportive effect of both zinc supplementation and deprivation on the metabolic switch during T cell activation, adding another level of immune regulation by zinc.

The Role of Zinc in GM-CSF-Induced Signaling in Human Polymorphonuclear Leukocytes.

SCOPE: Zinc is suggested to be necessary for functional signaling induced by certain growth factors. The granulocyte-macrophage colony-stimulating factor (GM-CSF) is a key factor for differentiation and activation of myeloid cells. This report analyses the impact of different zinc concentrations on GM-CSF-induced signaling in mature polymorphonuclear leukocytes (PMN). METHODS AND RESULTS: As measured by flow cytometry, zinc increases surface GM-CSF receptor (GM-CSFR) in PMN, whereas monocytes respond with decreased GM-CSFR surface expression. Since total cellular GM-CSFR expression remains unaffected, the observed zinc-induced GM-CSFR surface dynamics may be explained by receptor redistribution. In PMN, zinc enhanced phosphorylation of mitogen-activated protein kinases (MAPK) in a dose-dependent manner as found in western blot. Zinc-induced MAPK phosphorylation is additionally augmented by moderate GM-CSF stimulation. CONCLUSION: The present study demonstrates the opposing influence of zinc on GM-CSFR surface expression in monocytes and PMN. Zinc and GM-CSF, use in optimized concentrations, augment MAPK signaling, and increase expression of MAPK-induced myeloid cell leukemia-1 (Mcl-1) in PMN. Thus, this study concludes that zinc strengthens growth factor-induced signaling. Hence, the study provides a basis for further in vivo studies, focusing on the therapeutic value of zinc in patients with a disturbed GM-CSF signaling.

How acute physical and psychological stress differentially influence the kynurenine pathway: A randomized cross-over trial.

Psychological stress is associated with the pathogenesis of several neuropsychiatric disorders. In contrast, physical stress, as provoked by exercise, counteracts symptoms and potentially also disease progression. The kynurenine pathway, which is imbalanced in neuropsychiatric disorders, responds to both psychological and physical stress. Here, we compared the acute effects of psychological versus physical stress on the kynurenine pathway and inflammatory mediators. Thirty-five healthy males (mean age: 24.09±3.39 years) underwent both the Trier Social Stress Test (psychological stressor) and the Wingate-Test (physical stressor). The kinetics of tryptophan and its metabolites as well as cytokines IL-6, IFN-γ, TNF-α, and IL-10 were measured before and after the two stress conditions. After both stressors, there was a significant change over time for the kinetics of tryptophan metabolites and for cytokines. Furthermore, the reactivity of kynurenine pathway metabolite ratios and cytokines was statistically greater after physical stress than after psychological stress. The increased metabolic flux towards kynurenic acid following acute physical stress suggests an exercise-induced neuroprotective mechanism. Despite the paradoxical influence of both stressors on neuropsychiatric diseases, the acute kynurenine pathway reactivity appears to be similar, although effects were more pronounced in response to physical stress.

Retrospective observational study evaluating zinc plasma level in patients undergoing thoracoabdominal aortic aneurysm repair and its correlation with outcome.

Thoracoabdominal aortic aneurysm (TAAA) repair is related to a relevant morbidity and in-hospital mortality rate. In this retrospective observational single-center study including serum zinc levels of 33 patients we investigated the relationship between zinc and patients' outcome following TAAA repair. Six patients died during the hospital stay (18%). These patients showed significantly decreased zinc levels before the intervention (zinc levels before intervention: 60.09 µg/dl [survivors] vs. 45.92 µg/dl [non-survivors]). The post-interventional intensive care SOFA-score (Sepsis-related organ failure assessment) (at day 2) as well as the SAPS (Simplified Acute Physiology Score) (at day 2) showed higher score points in case of low pre-interventional zinc levels. No significant correlation between patient comorbidities and zinc level before intervention, except for peripheral arterial disease (PAD), which was significantly correlated to reduced baseline zinc levels, was observed. Septic shock, pneumonia and urinary tract infections were not associated to reduced zinc levels preoperatively as well as during therapy. Patients with adverse outcome after TAAA repair showed reduced pre-interventional zinc levels. We speculate that decreased zinc levels before intervention may be related to a poorer outcome because of poorer physical status as well as negatively altered perioperative inflammatory response.