Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticosteroids (GC) are the true immunomodulators that can depress and enhance immune reactions. Hormone-activated GC receptors (GCR) change the transcription of many genes, resulting in modified immune responses. The direction of immunomodulation under which GC act depends on their level, the quantity and state of GCR, the amount of different cytokines and cytokine receptors and other immunoactive molecules. The modulation of proinflammatory (IL-1 beta, IL-6, TNF-alpha) cytokine production by human peripheral lymphocytes treated with a wide range of dexamethasone (10(-6)-10(-12) mol) in the serum-free culture medium was observed in the present study. Enhanced or suppressed cytokine release depends on GC doses, intermittent or continuous contact with the hormone and cell environment. The magnitude of changes in IL-1 beta and TNF-alpha production was similar (parallel stimulation or depression) while diminished TNF-alpha was observed simultaneously with enhanced IL-6 production and vice versa. The suppression of proinflammatory cytokine production by GC is well documented. The experimental conditions of increased cytokine release with dexamethasone in the serum-free culture medium can serve as a model of investigation in false results of steroid immunosuppression.
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PMID:[Increased proinflammatory cytokine production by human peripheral lymphocytes treated with glucocorticoids]. 1124 25

Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS-induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-alpha mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.
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PMID:Illness, cytokines, and depression. 1126 75

It is now widely accepted that psychological stress and psychiatric illness can compromise immune function. Furthermore the mechanisms whereby such changes occur are probably associated with the activities of the cytokines and other inflammatory mediators of the immune system which are known to initiate changes in behaviour. This review aims to summarise the experimental and clinical evidence that implicates the pro-inflammatory cytokines in the pathological changes seen in major depression and in Alzheimer's disease (AD). In major depression, evidence is provided to show that both activation (e.g., macrophage activity, acute phase proteins) and inhibition (e.g., natural killer cell activity) of the immune system occur. Many of the behavioural changes seen in depression are simulated by three pro-inflammatory cytokines (IL-1, IL-6 and TNF-alpha), which may produce their impact on the brain by activating cyclooxygenase, nitric acid synthase and corticotrophin releasing factor. Effective antidepressant treatments largely attenuate the immune changes thereby raising the possibility that the normalisation of central biogenic amine function that are conventionally implicated in the cause of depression may be secondary to those of the pro-inflammatory cytokines. With respect to AD, while the cause(s) are unknown, there is both experimental and clinical evidence to suggest that inflammatory processes in the brain caused in particular by TNF-alpha together with the subsequent rise in free radicals, are instrumental in causing the pathological changes which underlie the disease. Evidence in favour of the inflammatory hypothesis is supported by the finding that nonsteroidal anti-inflammatory drugs slow down the progression of the disease.Although, more research is needed into the inter-relationships between the various pro-inflammatory cytokines and the behavioural changes invoked in major depression and AD, the immunological hypothesis has been important in stimulating new concepts regarding the causes of the pathological changes in these diseases and how effective drug treatments may attenuate them.
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PMID:Changes in the immune system in depression and dementia: causal or co-incidental effects? 1133 99

Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and nitric oxide (NO) may play a role in lipopolysaccharide (LPS)-induced cardiac depression. Toll-like receptor-4 (TLR-4) mediates the cytokine response to LPS in immune cells. TLR-4 also is expressed in human and murine myocardial tissue. Therefore, the hypothesis that LPS induces proinflammatory cytokines in the heart via TLR-4 was tested. C3H/HeJ (TLR-4 deficient) and C3HeB/FeJ mice were studied. LPS induced a robust increase in myocardial TNF-alpha and IL-1beta mRNA in C3HeB/FeJ mice. The response in C3H/HeJ mice was blunted and delayed. Myocardial TNF-alpha and IL-1beta protein levels were higher in C3HeB/FeJ mice, as were inducible NO synthase protein and NO production. Activation of myocardial NF-kappaB was observed within 30 min in C3HeB/FeJ mice but not in C3H/HeJ mice. These findings suggest that myocardial TLR-4 is involved in signaling cytokine production within the heart during endotoxic shock.
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PMID:In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: the role of toll-like receptor-4. 1134 10

The effects of very low doses of endotoxin (20 ng/kg/h for 8 h) were evaluated in a conscious sheep model in which introducers for catheters for monitoring pressure and ventricular dimensions had been previously inserted so that the studies could be performed without anesthesia and without a previous thoracotomy. Analog data was obtained at hourly intervals for 10 h and again at 24 h and was used to construct a beat-to-beat analysis of left ventricular performance. Only minimal effects were observed on heart rate, end diastolic pressure, arterial pressure, cardiac output, or cardiac work, although there was a significant rise in pulmonary artery pressure at 1 h of infusion. Despite the absence of changes in heart rate, preload, or afterload, maximal dp/dt decreased significantly by 4 h and remained decreased for the 10-h observation period; it returned to normal at 24 h. End systolic elastance decreased at 6 h and Pmax/EDV, a new indicator of performance, also decreased at 6 and 9 h. Thus, systolic performance decreased. Negative dp/dt did not change, but time for relaxation from 80% to 20% of peak ventricular pressure increased significantly at 5, 6, and 8 h. Plasma TNF-alpha was also measured and showed a significant rise at 2 h, but rapidly decreased thereafter. These results indicate an early depression of myocardial contractility and distensibility at doses of endotoxin insufficient to produce measurable effects on arterial pressure or cardiac output.
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PMID:Beat-to-beat evaluation of cardiac function in low-dose endotoxemia using a conscious sheep model. 1169 75

Depression is a common problem in multiple sclerosis (MS) and affects about 50% of MS patients. Since a dysregulation of cytokine levels has been implicated in the pathogenesis of MS and alterations in cytokine serum levels have been found in depressive illness, we examined the relationship between depressive symptoms, cytokine mRNA expression levels of Th1-type and Th2-type cytokines and neurological disability among early diagnosed MS patients in a prospective study. Sixteen patients with clinically or laboratory supported MS were assessed using the Beck Depression Inventory (BDI) and the Kurtzke Expanded Disability Status Scale (EDSS). Cytokine mRNA in whole blood was serially determined by a new quantitative polymerase chain reaction (PCR) method. BDI sum scores (2,9 fold) and the expression levels of tumor necrosis factor-alpha (TNF-alpha; 4 fold), interferon-gamma (IFN-gamma; 4,6 fold) and interleukin-10 (IL-10; 6,1 fold) mRNA were increased in MS patients during an acute attack compared to age and sex matched healthy controls. We detected a significant positive correlation between TNF-alpha (r=0.55) and interferon-gamma (r=0.54) mRNA expression and the BDI sum scores during an acute attack in MS patients. At follow-up after 3-6 months, only TNF-alpha mRNA expression was correlated with BDI sum scores (r=0.62 resp. r=0.31). No correlation of the BDI sum scores with Th2-type cytokine mRNA expression for interleukin-4 (IL-4) and interleukin-10 (IL-10) or with the extent of neurological disability was observed. The possible contribution of Th1-type cytokines to the development of depression in MS is discussed.
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PMID:Expression of tumor necrosis factor-alpha and interferon-gamma mRNA in blood cells correlates with depression scores during an acute attack in patients with multiple sclerosis. 1208 60

This review article integrates empirical findings from various scientific disciplines into a proposed psychoneuroimmunological (PNI) model of the acute coronary syndrome (ACS). Our starting point is an existing, mild, atherosclerotic plaque and a dysfunctional endothelium. The ACS is triggered by three stages. (1) Plaque instability: Pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha) and chemoattractants (MCP-1, IL-8) induce leukocyte chemoattraction to the endothelium, and together with other triggers such as the CD40L-CD40 co-stimulation system activate plaque monocytes (macrophages). The macrophages then produce matrix metalloproteinases that disintegrate extra-cellular plaque matrix, causing coronary plaque instability. Acute stress, hostility, depression and vital exhaustion (VE) have been associated with elevated pro-inflammatory cytokines and leukocyte levels and their recruitment. (2) Extra-plaque factors promoting rupture: Neuro-endocrinological factors (norepinephrine) and cytokines induce vasoconstriction and elevated blood pressure (BP), both provoking a vulnerable plaque to rupture. Hostility/anger and acute stress can lead to vasoconstriction and elevated BP via catecholamines. (3) Superimposed thrombosis at a ruptured site: Increases in coagulation factors and reductions in anticoagulation factors (e.g. protein C) induced by inflammatory factors enhance platelet aggregation, a key stage in thrombosis. Hostility, depression and VE have been positively correlated with platelet aggregation. Thrombosis can lead to severe coronary occlusion, clinically manifested as an ACS. Thus, PNI processes might, at least in part, contribute to the pathogenesis of the ACS. This chain of events may endure due to lack of neuroendocrine-to-immune negative feedback stemming from cortisol resistance. This model has implications for the use of psychological interventions in ACS patients.
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PMID:Molecular and cellular interface between behavior and acute coronary syndromes. 1223 62

The hippocampus is one of the most studied sites for understanding the cellular and molecular mechanisms underlying long-term potentiation (LTP) and long-term depression (LTD), mechanisms believed to underlie the formation and storage of memories. The early-phases of LTP and LTD have been most intensively studied and have been shown to involve the activation of several kinases and phosphatases, respectively. The factors involved in the later stages have largely yet to be elucidated. We have focused our attention on the transcription factor NF-kappaB as a possible factor involved in such late-phase processes, and have developed both immunocytochemistry and electrophoretic mobility shift assay (EMSA) to measure the activated forms of this factor. This is important as many of the studies in this area are performed in vitro and to our knowledge quantitative assessment has not previously being deemed feasible in slice work. The pro-inflammatory cytokines TNF-alpha and IL-1beta both led to pronounced nuclear activation of NF-kappaB in the dentate granule cells as demonstrated by immunostaining and EMSA, respectively. Electrophysiological measurements taken from slices treated with TNF-alpha showed that it inhibited LTP (field excitatory post-synaptic potentials (fEPSP) 116+/-10%, n = 9, 60 min post-tetanus compared to control fEPSP 185+/-9%, n = 6; P < 0.001). The neurotransmitter L-glutamate also led to activation of NF-kappaB and electrophysiology recordings showed a small but sustained increase in synaptic transmission (fEPSP 106+/-12%, 30 min post-drug). These methods provide valuable tools to forward our understanding of the role of NF-kappaB in plasticity as well as in many neurological disorders being mimicked by in vitro studies.
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PMID:Methods of detection of the transcription factor NF-kappa B in rat hippocampal slices. 1232 22

TNF-alpha expression is elevated in a variety of neuropathologies, including multiple sclerosis, cerebral malaria and HIV encephalitis. However, the consequences of such high cerebral TNF-alpha expression remain unresolved. Here, using MRI, we demonstrate that a focal intrastriatal injection of TNF-alpha causes a significant, acute reduction (15-30%) in cerebral blood volume (CBV), which is dependent on TNF-alpha-type 2 receptor (TNFR2) activation, and can be ameliorated by pre-treatment with a non-specific endothelin (ET) receptor antagonist. An acute breakdown of the blood-cerebrospinal fluid barrier (B-CSF-B) and a delayed breakdown of the blood-brain barrier (BBB) were also observed using contrast-enhanced MRI. Furthermore, a significant reduction in tissue water diffusion was apparent 24 h after intrastriatal injection of TNF-alpha injection, which may indicate compromise of tissue energy metabolism. Prolonged expression of endogenous TNF-alpha, achieved through the use of an adenoviral vector expressing TNF-alpha cDNA (Ad5TNF-alpha(m)), caused a sustained depression in CBV in accordance with the single TNF-alpha bolus data. These findings identify vasoconstriction, disrupted tissue homeostasis and damage to the BBBs as adverse effects of TNF-alpha within the brain, and suggest that antagonists of the endothelin and TNF-alpha type 2 receptors may be therapeutic in TNF-alpha-associated neuropathologies.
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PMID:TNF-alpha reduces cerebral blood volume and disrupts tissue homeostasis via an endothelin- and TNFR2-dependent pathway. 1239 Sep 71

Alterations in cellular immune function are associated with depression and have been related to changes in endocrine function. We carried out a study to: (i) reliably assess the hypothalamic-pituitary-adrenal (HPA) axis function in treatment resistant depression (TRP); (ii) evaluate whether depression was associated with changes on T-cell proliferation and cytokine production; and (iii) assessed the sensitivity of lymphocytes to glucocorticoids (GC)s in vitro. Thirty-six pharmacologically treated inpatients diagnosed with TRP and 31 healthy controls took part in the study. Salivary cortisol was measured hourly from 0800 to 2200 h both before and after dexamethasone (DEX) intake and the patients were classified into HPA axis suppressors and nonsuppressors. The following were measured in vitro: (a) phytohemagglutinin-induced T-cell proliferation; (b) cytokine production (interleukin-2 and tumor necrosis factor-alpha, TNF-alpha); and (c) lymphocyte sensitivity to both cortisol and DEX. Basal morning cortisol levels from patients and controls did not differ nor did their T-cell proliferation and cytokine production. Ten out of 36 patients were classified as nonsuppressors and presented a significantly higher post-DEX salivary cortisol levels than suppressors, 82.0 vs 8.9 nM/l/h (p <0.001). Cells of nonsuppressors produced significantly less TNF-alpha compared to suppressors, 299.8 vs 516.9 pg/ml (p < 0.05). Remarkably, GC-induced suppression of lymphocyte proliferation and cytokine production were generally less marked in depressives compared with controls. Our data indicate that alterations in immune function and steroid regulation associated with depression are not related to elevated basal levels of cortisol and suggest that lymphocyte steroid resistance may be associated with TRP.
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PMID:Altered glucocorticoid immunoregulation in treatment resistant depression. 1244 36


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