Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroendocrine mechanisms are involved in modulation of the immune system, but the mode of action of the complex interplay between hormones and the immune system is only partially understood. This study examines the role of cortisol in monocyte differentiation and function, with regard to interleukin-1 beta (IL-1 beta) expression. The differentiation of the human histiocytic lymphoma cell line U 937 into macrophage-like cells by phorbol ester [phorbol myristate acetate (PMA)] is inhibited by cortisol. Some cells remain in suspension and continue to divide; others stop proliferation, but do not undergo full morphological differentiation. When cells are washed after 3 days to remove PMA and cortisol, all cells stop dividing and become fully differentiated. The PMA, therefore, commits the cells to differentiate even after its removal, while cortisol is only suppressive when present. Differentiated cells are shown to produce IL-1 beta mRNA when stimulated with lipopolysaccharide. This effect is inhibited by cortisol in a dose-dependent manner. After removal of cortisol, the least differentiated cells that remained in suspension were found to be overproducers of IL-1 beta mRNA after stimulation with lipopolysaccharide. This suggests that PMA induces a buildup of transcription-activating factors that were suppressed in the presence of cortisol. We conclude that the adrenal glucocorticoids that are elevated in acute stress conditions or major depression attenuate the differentiation and function of monocytes.
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PMID:Inhibition of macrophage differentiation and function by cortisol. 236 81

Previous studies have shown that LPS and cytokines modulate the binding of glucocorticoids (GCs) in the CNS, and therefore may affect the negative feedback exerted by GCs. In this study, we investigated the effect of lipopolysaccharide (LPS) on the inhibitory action of GCs upon the adrenocortical response to a neural stressful stimulus. Male rats were treated with either LPS (50 micrograms/kg) or saline for 5 consecutive days. Two days later, the LPS- and saline-treated rats were injected intraperitoneally with either dexamethasone (20 micrograms/kg) or saline and sacrificed 3.5 h later, after exposure to acute stressful photic stimulation. In saline-pretreated rats, photic stimulation caused a 5-fold increase in serum corticosterone levels compared to basal levels, and pretreatment with dexamethasone completely abolished this response. In LPS-pretreated rats, corticosterone levels following photic stimulation increased 20-fold, and dexamethasone was ineffective. Additional experiments were conducted to examine whether the impairment in the negative feedback was specific to the prolonged LPS treatment, rather than to LPS-induced hypersecretion of GCs. In groups of rats which were exposed to either daily acoustic stress or daily administration of corticosterone (5 mg, twice daily) for 5 days, the pattern of corticosterone secretion mimicked the corticosterone secretion induced by LPS. In these groups, the adrenocortical response to acute photic stimulation and the effect of dexamethasone were similar to saline-pretreated controls. These results suggest that LPS impairs the negative feedback of either endogenous or exogenous GC upon the adrenocortical response to stress. This finding may be relevant to the enhanced adrenocortical activity associated with sepsis and major depression.
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PMID:Effects of bacterial endotoxin on the glucocorticoid feedback regulation of adrenocortical response to stress. 926 46

There is some evidence that major depression--in particular, treatment-resistant depression (TRD)--is accompanied by activation of the inflammatory response system and that proinflammatory cytokines may play a role in the etiology of depression. This study was carried out to examine the effects of antidepressive agents, i.e., imipramine, venlafaxine, L-5-hydroxytryptophan, and fluoxetine on the production of interferon-gamma (IFN-gamma), a proinflammatory cytokine, and interleukin-10 (IL-10), a negative immunoregulatory cytokine. Diluted whole blood of fluoxetine-treated patients with TRD (mean age, 50.6+/-3.9 years) and age-matched healthy controls (mean age, 51.6+/-1.7 years) and younger healthy volunteers (mean age, 35.4+/-9.6 years) was stimulated with phytohemagglutinin (1 microg/mL) and lipopolysaccharide (5 microg/mL) for 48 hours with and without incubation with the antidepressants at 10-6 M and 10(-5) M. IFN-gamma and IL-10 were quantified by means of enzyme-linked immunoassays. The ratio of IFN-gamma to IL-10 production by immunocytes was computed because this ratio is of critical importance in determining the capacity of immunocytes to activate or inhibit monocytic and T-lymphocytic functions. All four antidepressive drugs significantly increased the production of IL-10. Fluoxetine significantly decreased the production of IFN-gamma. All four antidepressants significantly reduced the IFN-gamma/IL-10 ratio. There were no significant differences in the antidepressant-induced changes in IFN-gamma or IL-10 between younger and older healthy volunteers and TRD patients. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-noradrenaline reuptake inhibitors, as well as the immediate precursor of serotonin, have a common, negative immunoregulatory effect by suppressing the IFN-gamma/IL-10 production ratio. It is suggested that the therapeutic efficacy of antidepressants may be related to their negative immunoregulatory effects.
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PMID:Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio. 1127 Sep 17

Major depression is accompanied by an activation of the inflammatory response system (IRS) and antidepressants may have immunoregulatory activities. This study was carried out to compare the effect of imipramine, mianserin and lithium on the in vitro production of Th1-like cytokines, such as IL-2, IFN-gamma, lymphotoxin and Th2-like cytokines such as IL-4, IL-10 as well as IL-12 and TGF-beta. Peripheral blood mononuclear cells (PBMC) of 16 healthy volunteers were stimulated with polyclonal activators (phytohemagglutinin with lipopolysaccharide PHA + LPS) with or without incubation with imipramine, mianserin (1 microM) or lithium (1 mM). Imipramine and mianserin exhibited similar activities enhancing unstimulated IFN-gamma and IL-10 production. In PHA + LPS-stimulated PBMC both antidepressants inhibited IFN-gamma, IL-2 and lymphotoxin production (Th1-like cytokines) as well as IL-12 and IL-4 production. Under the same in vitro conditions, both antidepressants stimulated production of negative immunoregulatory cytokines such as IL-10 and TGF-beta. Lithium differed significantly from imipramine and mianserin, as it enhanced IL-2, IFN-gamma, IL-10 and TGF-beta production and inhibited only IL-4. All three examined antidepressants reduced IFN-gamma/IL-10 ratio. None of the antidepressants at the used concentrations induced apoptosis in PBMC so those changes in cytokine production were not the result of selective killing of certain cell subpopulations. Imipramine and mianserin at high concentrations negatively influenced reactive oxygen species (ROS) production in neutrophils, however, at concentrations in the therapeutical range none of the antidepressants used influenced "oxidative burst" in neutrophils. The results indicate that antidepressants exert immunoregulatory effects on human leukocyte functions, especially on cytokine production.
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PMID:In vitro immunoregulatory effects of antidepressants in healthy volunteers. 1450 14

Fluoxetine is a selective serotonin reuptake inhibitor that is widely used in the treatment of major depression including after stroke. In this study, we tested whether fluoxetine protects neuronal death in a rat cerebral ischemia model of middle cerebral artery occlusion (MCAO). The administration of fluoxetine intravenously (10 mg/kg) at 30 min, 3 hr, or 6 hr after MCAO reduced infarct volumes to 21.2+/-6.7%, 14.5+/-3.0%, and 22.8+/-2.9%, respectively, of that of the untreated control. Moreover, the neuroprotective effect of fluoxetine was evident when it was administered as late as 9 hr after MCAO/reperfusion. These neuroprotective effects were accompanied by improvement of motor impairment and neurological deficits. The fluoxetine-treated brain was found to show marked repressions of microglia activation, neutrophil infiltration, and proinflammatory marker expressions. Moreover, fluoxetine suppressed NF-kappaB activity dose-dependently in the postischemic brain and also in lipopolysaccharide-treated primary microglia and neutrophil cultures, suggesting that NF-kappaB activity inhibition explains in part its anti-inflammatory effect. These results demonstrate that curative treatment of fluoxetine affords strong protection against delayed cerebral ischemic injury, and that these neuroprotective effects might be associated with its anti-inflammatory effects.
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PMID:Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect. 1885 41

It is firmly established that women experience major depression (MD) at roughly twice the rate of men and that dysregulation of the immune system is associated with the appearance and course of this condition. In the present study, we sought to identify whether "sickness behavior", an inflammatory model of MD, is characterized by sexual dimorphism by focusing on both neurochemical and behavioral responses. Therefore, we investigated the serotonergic and dopaminergic activity of various brain regions implicated in the pathophysiology of affective disorders (hypothalamus, hippocampus, prefrontal cortex, amygdala and striatum) in response to a mild lipopolysaccharide (LPS) challenge, in rats of both sexes. According to our results, at 2 h post-LPS administration (100 microg/kg i.p.), the neurochemical substrate was primarily altered in female rats with the serotonergic function being markedly enhanced in all brain regions examined. Dopaminergic activation following immune system sensitization with LPS was not apparent in male rats and only modest in female rats with the exception of striatum. LPS administration also affected sickness-associated behaviors to a different extent in male and female rats, as assessed in the forced swim test (FST), the hot plate test (HPT) and the open-field arena. LPS-treated female rats coped better with the stressful FST procedure, as evidenced by an increase in swimming duration. The effects of LPS treatment appeared to be more robust in male rats, as far as suppression of locomotor activity is concerned, while the antinociceptive properties of LPS were evident in both sexes though showing sex-dependent kinetics. Moreover, when traditional measures of sickness (i.e. sucrose consumption, social exploration, food intake) were assessed, males and females appeared to be similarly affected, except for food intake. These data are the first to demonstrate that the serotonergic system is affected to a greater extent in female rats at 2 h post-LPS administration and further contribute to our understanding regarding sexual dimorphism upon sickness establishment.
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PMID:Neurochemical and behavioral alterations in an inflammatory model of depression: sex differences exposed. 1940 13

Chronic stressors and inflammatory immune activation may contribute to pathophysiological alterations associated with both major depression and cardiovascular disease. The present study, conducted in mice, assessed whether a chronic stressor of moderate severity that induced an anhedonic effect, when coupled with a bacterial endotoxin, lipopolysaccharide (LPS), additively or interactively provoked circulating and heart atrial natriuretic peptide (ANP), a potentially useful diagnostic and prognostic tool in cardiac diseases. As well, given the potential role of inflammatory processes in both depression and cardiovascular disease, we assessed pro-inflammatory mRNA expression in heart in response to the stressor and the LPS treatments. Male CD-1 mice that had been exposed to a chronic, variable stressor over 4 weeks displayed reduced sucrose consumption, possibly reflecting the anhedonic effects of the stressor. Treatment with LPS (10mug) provoked increased circulating corticosterone levels in both chronically stressed and non-stressed mice. Moreover, ANP concentrations in plasma and in the left ventricle were increased by both the stressor and the LPS treatments, as were left atrial and ventricular cytokine (interleukin-1beta; tumor necrosis factor-alpha) mRNA expression. Further, these treatments synergistically influenced the rise of plasma ANP. A link may exist between stressor-provoked depressive features (anhedonia) and immune activation, with elevated levels of ANP, a potential marker of cardiovascular disturbance. These findings are consistent with the view that chronic stressors and inflammatory immune activation may represent a common denominator subserving the frequent comorbidity between these illnesses.
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PMID:Anhedonia and altered cardiac atrial natriuretic peptide following chronic stressor and endotoxin treatment in mice. 1960 44

Encephalopathy associated with septic shock as well as psychiatric disorders can be caused by the central nervous formation of reactive oxygen species (ROS) associated with inflammation. The systemic application of lipopolysaccharide (LPS, 100 mug/kg i.p.) also serves as a model for major depression and results in enhanced inflammatory processes. which are characterized by the stimulation of microglia or macrophages that then impair normal brain function. The aim of the present study was to analyze the effect of peripherally applied LPS on the central nervous formation of ROS and IL-6 in wild-type mice and in mice lacking the NADPH oxidase Nox2 subunit gp91phox. Microdialysis was performed in the striatum of the mice. Central nervous ROS were detected by electron spin resonance spectroscopy using 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH) as reactant, which was infused via a microdialysis probe. IL-6 was measured in microdialysis samples by an immunoassay. Finally, blood samples were taken by heart puncture to detect IL-6 in plasma. In the wild-type mice, LPS significantly increased the ROS formation in the striatum of wild-type mice and resulted in a significantly enhanced IL-6 production. In the mice lacking the NADPH oxidase Nox2 subunit gp91phox, LPS did not enhance ROS formation, while central IL-6 was significantly increased. IL-6 plasma values were enhanced in both types of mice. In conclusion, the gp91phox-containing NADPH oxidase complex is involved in the central nervous ROS formation after peripheral LPS stimulation and might be a pharmacological target in patients with septic shock.
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PMID:Lipopolysaccharide-induced radical formation in the striatum is abolished in Nox2 gp91phox-deficient mice. 1986 38

This paper reviews recent research on the contribution of the proinflammatory cytokine interleukin-1 (IL- 1) and the purine nucleoside adenosine in mediating behavioral depression and related symptoms of conservation-withdrawal in animal models of both major depression and illness. Activation of brain IL- 1 receptors appears to contribute to conservation withdrawal symptoms in animals treated with reserpine or lipopolysaccharide, suggesting a common underlying mechanism. Moreover, brain cytokine signaling is capable of recruiting adenosine signaling at adenosine A2A receptors, which directly mediate symptoms of behavioral depression. The adenosine receptors densely populate spiny GABAergic neurons in the striopallidal tract in the striatum and form part of an A2A/D2/mGLU receptor complex. Activation of these A2A receptors functionally uncouples dopamines excitatory motivation influence from ongoing behavior, leading to a state of conservation-withdrawal, and antagonism of the ventral medial striatum A2A receptors in reserpinated rats relieves symptoms of behavioral depression.
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PMID:Biochemical and anatomical substrates of depression and sickness behavior. 2068 1

Brain inflammation has a critical role in the pathophysiology of brain diseases of high prevalence and economic impact, such as major depression, schizophrenia, post-traumatic stress disorder, Parkinson's and Alzheimer's disease, and traumatic brain injury. Our results demonstrate that systemic administration of the centrally acting angiotensin II AT(1) receptor blocker (ARB) candesartan to normotensive rats decreases the acute brain inflammatory response to administration of the bacterial endotoxin lipopolysaccharide (LPS), a model of brain inflammation. The broad anti-inflammatory effects of candesartan were seen across the entire inflammatory cascade, including decreased production and release to the circulation of centrally acting proinflammatory cytokines, repression of nuclear transcription factors activation in the brain, reduction of gene expression of brain proinflammatory cytokines, cytokine and prostanoid receptors, adhesion molecules, proinflammatory inducible enzymes, and reduced microglia activation. These effects are widespread, occurring not only in well-known brain target areas for circulating proinflammatory factors and LPS, that is, hypothalamic paraventricular nucleus and the subfornical organ, but also in the prefrontal cortex, hippocampus, and amygdala. Candesartan reduced the associated anorexic effects, and ameliorated associated body weight loss and anxiety. Direct anti-inflammatory effects of candesartan were also documented in cultured rat microglia, cerebellar granule cells, and cerebral microvascular endothelial cells. ARBs are widely used in the treatment of hypertension and stroke, and their anti-inflammatory effects contribute to reduce renal and cardiac failure. Our results indicate that these compounds may offer a novel and safe therapeutic approach for the treatment of brain disorders.
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PMID:Angiotensin II AT1 receptor blockade ameliorates brain inflammation. 2115 Sep 13


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