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At least 1,081 records · Page 60Linked to original sources

PubMed2003

A role for Stat5 in CD8+ T cell homeostasis.

Cytokine signals are known to contribute to CD8+ memory T cell homeostasis, but an exact understanding of the mechanism(s) has remained elusive. We have now investigated the role of Stat5 proteins in this process. Whereas Stat5a and Stat5b KO mice have decreased numbers of CD8+ T cells, Stat5-transgenic mice have an increased number of these cells. Stat5b-transgenic mice exhibit increased Ag-induced cell death of CD4+ T cells and augmented proliferation and Bcl-2 expression in CD8+ T cells, providing a basis for this finding. Moreover, CD8+ memory T cells are substantially affected by Stat5 levels. These findings identify Stat5 proteins as critical signaling mediators used by cytokines to regulate CD8+ T cell homeostasis.

Animals↗

PubMed2004

The Gads (GrpL) adaptor protein regulates T cell homeostasis.

Little is known about the role of the Gads (GrpL) adaptor protein in mature T cell populations. In this study we show that the effects of Gads deficiency on murine CD4(+) and CD8(+) T cells are markedly different. Gads(-/-) CD4(+) T cells were markedly deficient in the spleen and had an activated phenotype and a rapid turnover rate. When transferred into a wild-type host, Gads(-/-) CD4(+) T cells continued to proliferate at a higher rate than wild-type CD4(+) T cells, demonstrating a defect in homeostatic proliferation. Gads(-/-) CD8(+) T cells had a memory-like phenotype, produced IFN-gamma in response to ex vivo stimulation, and underwent normal homeostatic proliferation in wild-type hosts. Gads(-/-) T cells had defective TCR-mediated calcium responses, but had normal activation of ERK. Gads(-/-) CD4(+) T cells, but not CD8(+) T cells, had a severe block of TCR-mediated proliferation and a high rate of spontaneous cell death and were highly susceptible to CD95-induced apoptosis. This suggests that the rapid turnover of Gads(-/-) CD4(+) T cells is due to a defect in cell survival. The intracellular signaling pathways that regulate homeostasis in CD4(+) and CD8(+) T cells are clearly different, and the Gads adaptor protein is critical for homeostasis of CD4(+) T cells.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Perturbed homeostasis of peripheral T cells elicits decreased susceptibility to anti-CD3-induced apoptosis in prediabetic nonobese diabetic mice.

Activation-induced cell death (AICD) plays a key role in the homeostasis of the immune system. Autoreactive T cells are eliminated through AICD both from the thymus and periphery. In this study, we show that NOD peripheral T cells, especially CD8(+) T cells, display a decreased susceptibility to anti-CD3-induced AICD in vivo compared with T cells from diabetes-resistant B6, nonobese diabetes-resistant, and NOD.B6Idd4 mice. The susceptibility of NOD CD8(+) T cells to AICD varies in an age- and dose-dependent manner upon stimulation in vivo with either a mitogenic or nonmitogenic anti-CD3. NOD T cells preactivated by anti-CD3 in vivo are less susceptible than B6 T cells to TCR-induced AICD. Treatment of NOD mice with a mitogenic anti-CD3 depletes CD4(+)CD25(-)CD62L(+) but not CD4(+)CD25(+)CD62L(+) T cells, thereby resulting in an increase of the latter subset in the spleen. Treatment with a nonmitogenic anti-CD3 mAb delays the onset of T1D in 8.3 TCR transgenic NOD mice. These results demonstrate that the capacity of anti-CD3 to protect NOD mice from T1D correlates with its ability to perturb T cell homeostasis by inducing CD8(+) T cell AICD and increasing the number of CD4(+)CD25(+)CD62L(+) T cells in the periphery.

Aging↗

PubMed2005

Cutting edge: CD95 maintains effector T cell homeostasis in chronic immune activation.

The elimination of activated T cells is important to maintain homeostasis and avoid immunopathology. CD95 (Fas/APO-1) has been identified as a death mediator for activated T cells in vitro but the function of CD95 in death of mature T cells in vivo is still controversial. Here we show that triggering of the costimulatory TNF receptor family member CD27 sensitized T cells for CD95-induced apoptosis. CD95-deficient (lpr/lpr) T cells massively expanded and differentiated into IFN-gamma-secreting effector cells in transgenic mice that constitutively express the CD27 ligand, CD70. Concomitantly, CD95-deficient CD70 transgenic mice became moribund by 4 wk of age with severe liver pathology and bone marrow failure. These findings establish that CD95 is a critical regulator of effector T cell homeostasis in chronic immune activation.

Adoptive Transfer↗

PubMed2005

Stimulating lymphotoxin beta receptor on the dendritic cells is critical for their homeostasis and expansion.

The increased number of dendritic cells (DCs) inside lymphoid tissue may contribute to the enhanced priming of lymphocytes. The homeostasis of splenic DCs has mostly been attributed to their migration to the spleen via the chemokine microenvironment induced by lymphotoxin beta receptor (LTbetaR) signaling on splenic stromal cells. In this study we show that the lack of direct LTbetaR signaling on DCs is associated with the reduction of the number of DCs in the spleen independently of chemokine gradients. LTbetaR-/- mice have reduced DCs and reduced BrdU incorporation on DCs, and fewer DCs from LTbetaR-/- mice are detected in the spleen. Furthermore, increased expression of LIGHT (homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for herpes virus entry mediator on T cells) on T cells, a member of the TNF family (TNFSF14) and a ligand for LTbetaR, could dramatically increase the number of T cells and DCs, which leads to severe autoimmune diseases in a LTbetaR-dependent fashion. In vitro, LIGHT could directly promote accumulation of bone marrow-derived DCs. Furthermore, intratumor expression of LIGHT can dramatically expand DCs in situ, and inoculation of DCs into tumor tissues enhanced tumor immunity. Therefore, LTbetaR signaling on DCs is required for their homeostasis during physiology and pathological conditions, and increased LIGHT-LTbetaR interaction could stimulate DC expansion for T cell-mediated immunity.

Animals↗

PubMed2005

NF-kappaB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo.

Protein kinase B (PKBalpha/Akt1) a PI3K-dependent serine-threonine kinase, promotes T cell viability in response to many stimuli and regulates homeostasis and autoimmune disease in vivo. To dissect the mechanisms by which PKB inhibits apoptosis, we have examined the pathways downstream of PKB that promote survival after cytokine withdrawal vs Fas-mediated death. Our studies show that PKB-mediated survival after cytokine withdrawal is independent of protein synthesis and the induction of NF-kappaB. In contrast, PKB requires de novo gene transcription by NF-kappaB to block apoptosis triggered by the Fas death receptor. Using gene-deficient and transgenic mouse models, we establish that NF-kappaB1, and not c-Rel, is the critical signaling molecule downstream of the PI3K-PTEN-PKB signaling axis that regulates lymphocyte homeostasis.

Animals↗

PubMed2006

Innate immune cells contribute to the IFN-gamma-dependent regulation of antigen-specific CD8+ T cell homeostasis.

IFN-gamma has a dual function in the regulation of T cell homeostasis. It promotes the expansion of effector T cells and simultaneously programs their contraction. The cellular mechanisms leading to this functional dichotomy of IFN-gamma have not been identified to date. In this study we show: 1) that expansion of wild-type CD8+ T cells is defective in IFN-gamma-deficient mice but increased in IFN-gammaR-deficient mice; and 2) that contraction of the effector CD8+ T cell pool is impaired in both mouse strains. Furthermore, we show that CD11b+ cells responding to IFN-gamma are sufficient to limit CD8+ T cell expansion and promote contraction. The data presented here reveal that IFN-gamma directly promotes CD8+ T cell expansion and simultaneously induces suppressive functions in CD11b+ cells that counter-regulate CD8+ T cell expansion, promote contraction, and limit memory formation. Thus, innate immune cells contribute to the IFN-gamma-dependent regulation of Ag-specific CD8+ T cell homeostasis.

Animals↗

PubMed2006

Possible roles of the hereditary hemochromatosis protein, HFE, in regulating cellular iron homeostasis.

Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European descent. Over 83% of the cases of HH result from a single mutation of a Cys to Tyr in the HH protein. HFE. This mutation causes a recessive disease resulting in an accumulation of iron in selected tissues. Iron overload damages these organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. The mechanism by which HFE influences iron homeostasis in cells and in the body remains elusive. Lack of functional HFE in humans produces the opposite effects in different cell types in the body. In the early stages of the disease. Kupffer cells in the liver and enterocytes in the intestine cells are iron depleted and have low intracellular ferritin levels, whereas hepatocytes in the liver are iron overloaded and have high intracellular iron levels. This review gives the background and a model as to possible mechanisms of how HFE could exert different effects on iron homeostasis in different cell types.

Animals↗

PubMed1999

Different influences of classical antipsychotics and clozapine on glucose-insulin homeostasis in patients with schizophrenia or related psychoses.

BACKGROUND: The aim of this study was to investigate the influence of classical antipsychotics and the atypical antipsychotic agent clozapine on glucose-insulin homeostasis to explain possible mechanisms behind weight gain associated with antipsychotic treatment. METHOD: Twenty-eight patients on therapy with classical antipsychotics and 13 patients treated with clozapine (all meeting DSM-III-R criteria for schizophrenia or related psychoses) were studied. Fasting blood samples for glucose and insulin, as well as for 2 markers of the glucose-insulin homeostasis, i.e., the growth hormone (GH)-dependent insulin-like growth factor I (IGF-I) and the insulin-dependent insulin-like growth factor binding protein-1, were analyzed. Body mass index (BMI) was calculated and serum concentrations of the different antipsychotic drugs were measured. In addition, the relationship between the endocrine parameters and drug serum concentrations was examined. RESULTS: The insulin levels were positively correlated to the serum concentration of clozapine, whereas no correlations were found between insulin and the serum concentrations of perphenazine (N = 12) or zuclopenthixol (N = 9). Insulin elevation was seen in the patients receiving clozapine more frequently than in the patients receiving classical antipsychotics. In addition, the median level of IGF-I was significantly lower in the patients receiving clozapine than in the patients receiving classical antipsychotics. No significant difference in BMI was found between the 2 patient groups, and all patients but 1 were normoglycemic. CONCLUSION: The correlation between insulin and the clozapine concentration indicates a probable influence of clozapine on insulin secretion. The normal blood glucose levels in the clozapine group support the theory that clozapine induces concentration-dependent insulin resistance with secondary increased insulin secretion. In addition, lower median level of IGF-I in patients receiving clozapine compared with patients receiving classical antipsychotics points to a lower GH secretion in the clozapine group. This impaired GH secretion together with the clozapine-induced insulin resistance might be mechanisms behind weight gain during clozapine therapy.

Adult↗

PubMed2006

CDK control of membrane-bound organelle homeostasis.

In eukaryotes, the copy number and size of any given organelle compartment remain constant in dividing cells, underlying a tight coordination between cell division and organelle homeostasis. However, in most cases the mechanisms for this coordination remain mysterious. Here we outline a few cases where the cell cycle machinery directly impacts on organelle homeostasis, with emphasis on the control of vacuolar (lysosomal) copy number and size in budding yeast. We also discuss aspects of organelle biology that can profoundly affect certain cell cycle parameters, such as cell size.

Cyclin-Dependent Kinases↗

PubMed1999

[Homeostasis of antioxidant status in hemodialysis patients].

Oxidative stress, which occurs when there is excessive free-radical production or low antioxidant levels, makes significant contributions to pathogenesis in many human diseases. Cardiovascular disease is the major cause of mortality in patients receiving hemodialysis. For these patients, oxidative stress and increased lipid peroxidation may contribute to increased risk of atherosclerosis. The aim of this study was to determine if hemodialysis patients were associated with disturbance of homeostasis of antioxidant status. In this experiment, total antioxidant status of serum is measured by its ability to inhibit generation of free radicals from 2,2'-amino-di-[3-ethylbenzthiazole sulphonate] by metmyoglobin and hydrogen peroxide. Status of radical scavengers, such as serum total protein, albumin, uric acid and total bilirubin, was also measured. Blood were collected from three different episodes of hemodialysis. In the first group (n = 29), blood were collected before and after hemodialysis. In the second group (n = 29), blood were collected after dialysis and before next hemodialysis. In the third group (n = 8), blood were collected before hemodialysis. After last hemodialysis, patients started ingesting vitamin C and blood were collected before next hemodialysis. There was a marked reduction of total antioxidant status after hemodialysis in the first group. There was a marked increase in total antioxidant status before next hemodialysis in the second group. High doses of vitamin C caused increase in total antioxidant status in the third group. In conclusion, disturbance of homeostasis of total antioxidant status were observed in patients receiving hemodialysis. This may play a role in the pathogenesis in these groups.

Adult↗

PubMed1999

Glutathione homeostasis in response to exercise training and nutritional supplements.

Glutathione plays a central role in the maintenance of tissue antioxidant defenses and in the regulation of redox sensitive signal transduction. In muscle cells, the level and redox status of GSH regulates activity of the redox sensitive transcription factor NF-kappaB. Physical exercise may cause oxidation of GSH in tissues such as the blood, skeletal muscle and liver. Endurance training strengthened GSH dependent tissue antioxidant defenses in most studies. Although studies investigating the effect of sprint training are few, current results show that sprint training may also have a beneficial effect on tissue GSH homeostasis. Skeletal muscle GSH level appears to be tightly regulated by the state of physical activity. Regular exercise enhances and chronic inactivity decreases the level of GSH in this tissue. N-acetyl-L-cysteine (NAC) and alpha-lipoic acid (LA) are two antioxidant dietary supplements that are able to enhance cellular GSH levels. Because LA can be recycled to its potent dithiol form, dihydrolipoate, by enzymes present in the human cell it has a clear advantage over NAC. Recently an improved form of LA, a positively charged analogue (LA-Plus), has been discovered. LA-Plus has more potent immuno-modulatory activity compared to LA. Both LA and NAC have been shown to have beneficial effects in protecting tissue GSH homeostasis against exercise induced oxidative stress.

Dietary Supplements↗

PubMed1999

Maintenance of homeostasis in coagulation during cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) represents a massive stimulus that overwhelms the body's homeostatic ability to buffer. Contact activation, the extrinsic cascade, and ongoing cellular interactions all must be considered to understand the coagulation dysfunction that occurs in CPB. Various aspects and the specific effects of these factors as well as their interrelationships are still poorly understood. Since we are dealing with a complex system, the way we approach our investigations must become more rather than less complex. Simply measuring peripheral blood levels of various proteins throughout CPB levels does not fit the important physiologic processes governing homeostasis, as production, clearance, redistribution, and dilution are all constantly at play. A recent study of prothrombin fragment F1.2 levels during CPB is provided as an illustration. Our increasing understanding of aprotinin's mechanisms of action has furthered our basic understanding of coagulation dysfunction in CPB. Further progress requires new thinking, more research, and increasingly complex approaches to the understanding of what drives homeostasis.

Anticoagulants↗

PubMed1999

Effect of stress-related hormones on inner ear fluid homeostasis and function.

HYPOTHESIS: Induction of suprathreshold levels of stress-related hormone by systemic administration of epinephrine can change inner ear fluid homeostasis and function. BACKGROUND: Meniere's disease is frequently associated with high levels of anxiety and other forms of psychological disturbance. Most clinicians agree that emotional stress or severe anxiety can precipitate relapse or aggravate the symptoms. In general, it is known that stress-related hormones such as epinephrine, norepinephrine, vasopressin, aldosterone, and cortisol are released into systemic circulation in response to stress. Significantly higher levels of plasma norepinephrine and vasopressin in patients with Meniere's disease have been reported. METHODS: Concentrations of sodium and potassium in perilymph were measured by a flame photometer after systemic infusion of epinephrine (6.3 microg/min for 3 hours). Control animals were treated with equal volumes of 0.9% physiologic saline. Compound action potentials (CAP) elicited by brief tone bursts were measured before and 3 hours after the infusion of epinephrine. For chronic studies, epinephrine (10 microg/d/kg) was given by osmotic pump implanted subcutaneously for 1, 2, 3, and 4 weeks, respectively. Click- and tone-evoked auditory brain responses (ABRs) were measured at 1, 2, 3, and 4 weeks after epinephrine administration. RESULTS: Concentrations of sodium and potassium increased significantly in perilymph (p < 0.001 and p < 0.01) after epinephrine infusion over controls. The osmolality increased significantly in serum and perilymph after epinephrine infusion. The CAP threshold was significantly elevated at all frequencies. The shift of the CAP threshold caused by epinephrine tended to be larger at higher frequencies. In chronic studies, epinephrine administration caused a transient 20 to 45 dB threshold shift that increased with time and was relatively constant across frequency. CONCLUSIONS: There is good evidence to suggest that stress-related hormones such as epinephrine can alter inner ear fluid homeostasis and auditory function. This study confirmed this hypothesis and illuminated the processes of alteration by demonstrating specific changes in perilymph composition and auditory function.

Animals↗

PubMed2000

Presenilin-1 mutation increases neuronal vulnerability to focal ischemia in vivo and to hypoxia and glucose deprivation in cell culture: involvement of perturbed calcium homeostasis.

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Studies of cultured neural cells suggest that PS1 mutations result in perturbed cellular calcium homeostasis and may thereby render neurons vulnerable to apoptosis. In light of evidence that metabolic impairment plays a role in AD, that cerebral ischemia may be a risk factor for AD, and that individuals with AD have increased morbidity and mortality after stroke, we examined the impact of a PS1 mutation on neuronal vulnerability to ischemic injury. We report that the extent of brain injury after focal cerebral ischemia reperfusion is increased, and behavioral outcome is worsened, in PS1 mutant knock-in mice compared to wild-type mice. Cultured cortical neurons from PS1 mutant mice exhibit increased vulnerability to glucose deprivation and chemical hypoxia compared to their wild-type counterparts. Calcium imaging studies demonstrated enhanced elevation of intracellular calcium levels after glucose deprivation and chemical hypoxia in neurons from PS1 mutant mice. Agents that block calcium release from IP(3)- and ryanodine-sensitive stores (xestospongin and dantrolene, respectively) protected against the endangering action of the PS1 mutation. Our data suggest that presenilin mutations may promote neuronal degeneration in AD by increasing the sensitivity of neurons to age-related ischemia-like conditions. The data further suggest that drugs that stabilize endoplasmic reticulum calcium homeostasis may prove effective in suppressing the neurodegenerative process in AD patients.

Alzheimer Disease↗

PubMed2000

Characteristics of spontaneous sleep with varying NREMS Episodes in healthy men: implication for delta activity homeostasis.

STUDY OBJECTIVES: We investigated the effects of the variation in the number of NREMS episodes on human sleep, in particular on delta activity distribution. PARTICIPANTS: Forty-one medication-free healthy men without personal or family history of psychiatric disorders. INTERVENTIONS: Subjects slept four consecutive nights, the last three were analyzed. Sleep was undisturbed and uninterrupted following self-selected schedule. RESULTS: With the exception of one night out of 123, subjects slept at least four NREMS episodes with 80% presenting five or six episodes per night. Yet, only 24% slept the same number of NREMS episodes across three nights. Shorter first NREMS episode was associated with greater number of NREMS episodes, and the total number of NREMS episodes was significantly predicted by the duration of the first one. Whether subjects slept four, five or six NREMS episodes, the proportion of TST spent in REMS, total delta power, total spectral power and the rate of delta power in the first NREMS episode did not differ between subjects. In each night, the distribution of delta activity across the first four NREMS episodes was not modified by the total number of NREMS episodes. CONCLUSION: When spontaneous sleep is allowed, healthy men mostly sleep beyond the fourth NREMS episode. Based on delta activity distribution across the first four episodes, we have demonstrated that the number of NREMS episodes does not modify delta sleep homeostasis. Only duration of first NREMS episode predicts the number of NREMS episodes slept. These results suggest that sleep homeostasis and NREMS-REMS alternation may be two independent processes.

Adult↗

PubMed2000

Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome.

Highly-active antiretroviral therapy (HAART) has lead to a dramatic decrease in the morbidity of patients infected with the human immunodeficiency virus (HIV). However, metabolic side effects, including lipodystrophy-associated (LD-associated) dyslipidemia, have been reported in patients treated with antiretroviral therapy. This study was designed to determine whether successful HAART was responsible for a dysregulation in the homeostasis of tumor necrosis factor-alpha (TNF-alpha), a cytokine involved in lipid metabolism. Cytokine production was assessed at the single cell level by flow cytometry after a short-term stimulation of peripheral blood T cells from HIV-infected (HIV(+)) patients who were followed during 18 months of HAART. A dramatic polarization to TNF-alpha synthesis of both CD4 and CD8 T cells was observed in all patients. Because it was previously shown that TNF-alpha synthesis by T cells was highly controlled by apoptosis, concomitant synthesis of TNF-alpha and priming for apoptosis were also analyzed. The accumulation of T cells primed for TNF-alpha synthesis is related to their escape from activation-induced apoptosis, partly due to the cosynthesis of interleukin-2 (IL-2) and TNF-alpha. Interestingly, we observed that LD is associated with a more dramatic TNF-alpha dysregulation, and positive correlations were found between the absolute number of TNF-alpha CD8 T-cell precursors and lipid parameters usually altered in LD including cholesterol, triglycerides, and the atherogenic ratio apolipoprotein B (apoB)/apoA1. Observations from the study indicate that HAART dysregulates homeostasis of TNF-alpha synthesis and suggest that this proinflammatory response induced by efficient antiretroviral therapy is a risk factor of LD development in HIV(+) patients.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Diminished calcium homeostasis and increased susceptibility to excitotoxicity of JS 3/16 progenitor cells after differentiation to oligodendroglia.

JS 3/16, derived from passaged oligodendroglial cultures prepared from rat cerebral white matter, differentiate from progenitors (OP) into complex process-bearing, galactocerebroside-positive but myelin basic protein-negative immature oligodendrocyte-like cells (ImO) after withdrawal of trophic factors. We found that JS 3/16 ImO are markedly more susceptible than OP to cell death after sustained alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptor (AMPA-GluR) activation. This excitotoxicity is preceded by loss of intracellular Ca(2+) homeostasis, which is more marked in ImO than OP. We identified three factors likely to contribute to the diminished Ca(2+) homeostatic capacity of ImO. First, signal intensities of immunoreactive GluR2, GluR3, and GluR4 AMPA-GluR subunits are increased 1.3- to 2.2-fold in ImO over OP without comparable changes in RNA editing and alternative splicing. Second, transcriptional levels of genes encoding Na(+)-Ca(2+) exchanger proteins and a plasma membrane ATPase (PMCA1), which are necessary for Ca(2+) extrusion across the plasma membrane, are lower in ImO than in OP. Third, ImO have more depolarized basal mitochondrial membrane potential (Delta Psi) than OP, and Delta Psi collapses within 15 min after onset of AMPA-GluR activation in almost all ImO, but not in the majority of OP. This Delta Psi collapse limits the capacity of ImO mitochondria to buffer the rise in intracellular Ca(2+) caused by AMPA-GluR activation. The JS 3/16 line provides a valuable system for analysis of intracellular Ca(2+) homeostasis and AMPA-GluR-mediated excitotoxicity in the oligodendroglial lineage.

Animals↗