UMLS:C0011570 - FACTA Search

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Kupffer cells are an important source of proinflammatory cytokines and contribute to the systemic inflammatory response observed following haemorrhagic shock. The systemic release of cytokines, such as TNF-alpha, IL-1 beta, IL-6, etc., has been associated with the decreased host immune and organ dysfunction following hypotension. Studies indicate that anterior pituitary hormone prolactin (PRL) plays an important role in the regulation of lymphocyte proliferation and macrophage function in vivo, as well as in vitro. However, it is not known what effects PRL administration has on Kupffer cells proinflammatory mediator release following haemorrhage. Therefore, it was the aim of this study to determine the effect of in vivo PRL administration on cytokine gene expression in Kupffer cells after haemorrhage. To study this, C3H/HeN male mice were bled to and maintained at a mean arterial pressure of 35 mmHg for 60 minutes, then resuscitated with shed blood, and segregated into two groups: one group was treated with PRL (100 micrograms/25 g body weight subcutaneously) while the other group received saline-vehicles. This was followed with lactated Ringer's solution (2 x the volume of shed blood). Two hours thereafter, the animals were sacrificed, Kupffer cells were isolated and stimulated with or without 10 micrograms/ml LPS for 1 hour. Total RNA was extracted and cytokine mRNA was detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results demonstrated that haemorrhage markedly increased the level of mRNA for IL-1 beta, IL-6, TGF-beta and TNF-beta in Kupffer cells. However, in vivo PRL treatment significantly decreased the cytokine gene expression in Kupffer cells following haemorrhage. This indicates that PRL may be useful in blunting the systemic inflammatory response associated with cell and organ depression following shock.
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PMID:Prolactin inhibits the increased cytokine gene expression in Kupffer cells following haemorrhage. 877 71

Recombinant human IL-6 (rhIL-6) is a pleiotropic cytokine with stimulatory actions on the hematopoietic system, the immune system and hepatocytes. Clinical interest in the use of this cytokine was raised because of its thrombopoietic properties and also because of its anti-tumor activity, which was shown in vitro and in the preclinical setting. Various studies show that doses up to 10 mu kg/kg/d rhIL-6 before and after chemotherapy are tolerable and the most frequent side-effects encountered consist of flu-like symptoms. Furthermore, a consistent decrease in hemoglobin was reported during rhIL-6 treatment. This was probably due to hemodilution, although a change in ferrokinetics, may also at least partly, explain the anemia. An evident increase of platelets has been observed in various studies. After chemotherapy, rh-IL6 seemed to hasten platelet recovery, without affecting platelet nadir. Preliminary data from studies investigating the value of rhIL-6 as an anti-tumor agent in renal cell carcinoma and melanoma reported low response rates, between 8 and 14%. The results of rhIL-6 in ameliorating chemotherapy induced bone-marrow depression and especially thrombocytopenia, are promising and merit further phase III studies.
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PMID:Potential use of recombinant human interleukin-6 in clinical oncology. 883 92

Because of its central role in metabolism and host defense mechanisms, the liver is thought to be a major organ responsible for the initiation of multiple organ failure during sepsis. It is, therefore, important to discuss whether hepatocellular dysfunction occurs during early sepsis and, if so, whether this occurs prior to hepatocellular damage as evidenced by elevation in serum enzyme levels. Because indocyanine green clearance has been demonstrated to be an early and extremely sensitive measure of active hepatocyte transport function, a technique for repeated measurement of hepatocellular function by in vivo indocyanine green clearance was developed in small animals, such as the rat. Studies have indicated that hepatocellular function is markedly depressed during early stages of polymicrobial sepsis despite the increased cardiac output and hepatic blood flow and decreased peripheral vascular resistance. The depression in hepatocellular function in early, hyperdynamic stages of sepsis does not appear to be due to any reduction in hepatic profusion but is associated with elevated levels of circulating proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-6. Furthermore, administration of recombinant murine TNF-alpha at a dose that does not reduce cardiac output and hepatic perfusion produces hepatocellular dysfunction and increases plasma levels of IL-6. Thus upregulation of TNF and/or IL-6 may be responsible for producing hepatocellular dysfunction during early, hyperdynamic stages of sepsis.
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PMID:Mechanism of hepatocellular dysfunction during hyperdynamic sepsis. 892 23

Antimalarials are beneficial therapeutic agents in systemic lupus and rheumatoid arthritis. These autoimmune diseases have abnormally low apoptosis of inflammatory cells. Both disorders have an abnormal angiogenesis. In the present report, antimalarials were demonstrated to selectively increase apoptosis of HUVECs in vitro. A 24-h exposure to 50 or 150 microM of the drugs was associated with a significant loss of substrate-adherent cells. Chloroquine exhibited an inhibitory effect on HUVEC proliferation over 7 days. Programmed cell death in HUVECs rendered nonadherent by chloroquine was confirmed by the induction of DNA fragmentation in floating cells. Northern blot analysis revealed a rapidly increased expression of the bcl-x(s) gene without any change in the expression of the bcl-2 gene, indicating that HUVECs under chloroquine were undergoing apoptosis. The onset of the apoptotic cascade in HUVECs appeared shortly after the addition of chloroquine. The effect of chloroquine on apoptosis was distinct from acute cell lysis and was restricted to HUVECs. Antimalarials also induced IL-1alpha production. In parallel, chloroquine alone did not increase the expression of IL-6. Anti-IL-1alpha Ab or IL-1Ra only marginally reversed chloroquine-induced depression of proliferation for the low drug concentration, but not the massive cell death effect at and above 50 microM. Taken together, these data may indicate that antimalarials repress angiogenesis. The autocrine mechanism involving IL-1alpha accounts only for a minor fraction of the full antiendothelial effect of chloroquine, which is mainly dependent on apoptosis.
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PMID:Mechanisms of action of antimalarials in inflammation: induction of apoptosis in human endothelial cells. 902 28

There is a strong interrelationship between the immune system, the central nervous system and psychological processes that are suggested to play a pivotal role in the pathogenesis of psychiatric disorders. In schizophrenia and depression, activation of the immune system has been observed repeatedly. Cytokines play a key role in immune activation. They are actively transported into the CNS, but also released from activated glia cells. Cytokines activate glia cells in the CNS to produce other cytokines, and a cascade of cytokine effects may be initiated by this mechanisms. During the past few years, the influence of the cytokines on dopaminergic, noradrenergic and serotonergic neurotransmission and also on the hormones of the hypothalamus-pituitary-adrenal axis has been elucidated. It suggests a pivotal role in psychological processes and psychiatric disorders. For example, in schizophrenia the IL-2 cerebrospinal fluid concentration shows a stronger relationship to the relapse probability than catecholamine metabolites. Although the hypersecretion of IL-2 in schizophrenia and of IL-6 in depression are suggested to play key roles for these disorders, a specificity of certain cytokines for certain psychiatric disorders seems unlikely. Psychomotor, sleep and sickness behavior are influenced by IL-1, disturbances of memory and attention by IL-2, but also by TNF-alpha. From the distribution of cytokine receptors in the CNS conclusions can be drawn regarding the influence of cytokines on psychological processes. The finding that norepinephrine stimulates activated astrocytes to produce IL-6 implies that the cytokine cascade may be activated by neuronal processes under certain conditions. This can lead to a molecular biological explanation of the influences of stress on the immune system. Lastly, influences of the cytokines on blood-brain barrier disturbances and further consequences resulting from the role of the cytokine network in the CNS are discussed.
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PMID:[Role of the cytokine network in the CNS and psychiatric disorders]. 913 17

Studies indicate that the liver, in particular the Kupffer cells, appear to be key contributors in the systemic inflammatory mediator response associated with shock and sepsis. Although several of these agents have been implicated as mediators of depressed immunoresponsiveness observed during sepsis, it remains unknown whether or not mediators released specifically by Kupffer cells play any significant role in producing the cellular dysfunction in distant organs. The aim of this study, therefore, was to determine whether or not acute Kupffer cell reduction before the onset of sepsis would protect splenic lymphocyte function. Kupffer cell number was reduced by prior (48 hours) treatment of mice with gadolinium chloride (GdCl2, 10 mg/kg of body weight, intravenously) or saline vehicle. Animals were then subjected to either sham-CLP (sham) or polymicrobial sepsis in the form of cecal ligation and puncture (CLP). Plasma and splenocytes were harvested at 2 or 24 hours after CLP. Splenocyte cultures were exposed to 2.5 micrograms concanavalin A/mL to assess their ability to release lymphokines. Cytokine (interleukin (IL)-2, IL-6, interferon-gamma, tumor necrosis factor-alpha) concentration in plasma or cell supernatants was assessed by bioassay. The results indicated that GdCl2 treated mice exhibited a marked reduction in circulating IL-6 levels at both 2 and 24 hours after CLP. Furthermore, the reduction of Kupffer cell number before the onset of sepsis completely prevented the depression of splenocyte IL-2 and interferon-gamma release, capacity. Thus mediators released by Kupffer cells during the systemic inflammatory response to polymicrobial sepsis play a significant role in producing immune dysfunction in resident splenic lymphocytes. In view of this, it appears that modulation of Kupffer cell hyperactivity during sepsis may be a novel approach for maintaining distant organ host defense mechanisms.
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PMID:Mechanism of splenic immunosuppression during sepsis: key role of Kupffer cell mediators. 919 70

Previous studies indicate a profound suppression of tumour necrosis factor alpha (TNF-gamma), IL-1 beta and IL-6 release capacity by peritoneal macrophage (PM phi), splenic macrophage (SM phi) and Kupffer cells (KC) during late sepsis. Such a loss of functional capacity may reduce the animal's ability to ward off infection. Prolactin is known to enhance monocyte, T- and B-lymphocyte immune responses under normal conditions and has beneficial effects on cell-mediated immunity after haemorrhage. In the respect, the dopamine antagonist, metoclopramide, has been reported to increase circulating prolactin levels. Nonetheless, it remains unknown whether prolactin or metoclopramide have any salutary effect on macrophage (M phi) cytokine gene expression following sepsis. To study this, male C3H/HeN mice were subjected to sepsis and immediately thereafter were treated with prolactin (100 micrograms/25 g body weight, s.c.), metoclopramide (100 micrograms/100 g BW, s.c.) or given saline. PM phi, SM phi and KC (only SM phi and KC in metoclopramide-treated animals) were isolated at 24 h after sepsis. The monolayers were stimulated with or without LPS 10 micrograms/ml for 1 h in vitro. Total RNA was extracted and mRNA was detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). A significant depression of constitutive and inducible mRNA levels of IL-1 beta, IL-6 and TNF-alpha in all three M phi populations were observed, when compared with shams (with exception of KC IL-6 mRNA in unstimulated cells). Prolactin as well as metoclopramide treatment after the onset of sepsis caused significant elevation of constitutive and inducible cytokine gene expression in all macrophages examined. Thus, prolactin and metoclopramide enhance the depressed M phi gene expression and may be useful in improving cell-mediated immunity during sepsis.
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PMID:Effects of prolactin and metoclopramide on macrophage cytokine gene expression in late sepsis. 919 78

Stressful environmental conditions are a major determinant of immune reactivity. This effect is pronounced in Australian National Antarctic Research Expedition populations exposed to prolonged periods of isolation in the Antarctic. Alterations of T cell function, including depression of cutaneous delayed-type hypersensitivity responses and a peak 48.9% reduction of T cell proliferation to the mitogen phytohaemagglutinin, were documented during a 9-month period of isolation. T cell dysfunction was mediated by changes within the peripheral blood mononuclear cell compartment, including a paradoxical atypical monocytosis associated with altered production of inflammatory cytokines. There was a striking reduction in the production by peripheral blood mononuclear cells of the predominant pro-inflammatory monokine TNF-alpha and changes were also detected in the production of IL-1, IL-2, IL-6, IL-1ra and IL-10. Prolonged Antarctic isolation is also associated with altered latent herpesvirus homeostasis, including increased herpesvirus shedding and expansion of the polyclonal latent Epstein-Barr virus-infected B cell population. These findings have important long-term health implications.
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PMID:Antarctic isolation: immune and viral studies. 924 93

Although hepatocellular function is depressed early after trauma and hemorrhage (which are associated with low flow conditions and tissue hypoxemia), it remains unknown whether hypoxemia without blood loss, produces hepatocellular dysfunction and, if so, whether IL-6 and PGE2 are associated with this dysfunction. To study this, rats were placed in a plastic box which was flushed with a gas mixture containing 6.3% O2:93.7% N2 or room air for 60 min, followed by their return to room air. At 0 and 4 h after hypoxemia, hepatocellular function (i.e., maximum velocity of indocyanine green clearance (Vmax) and the efficiency of the transport (Km)) was measured using an in vivo hemoreflectometer. Cardiac output was assessed by dye dilution technique. Tissue microvascular blood flow was determined by laser Doppler flowmetry. Plasma IL-6 and PGE2 were measured by bioassay and radioimmunoassay, respectively. The results indicate that hypoxemia produced a depression in hepatocellular function (i.e., decreased Vmax by 44-50% and Km by 55-68%) despite stable cardiac output and hepatic microcirculation at 0 and 4 h after hypoxemia. Moreover, hypoxemia resulted in a significant increase in plasma IL-6 (by 372%-389%) as well as PGE2 (by 38% at 0 h post-hypoxemia). Thus, hypoxemia observed after trauma and hemorrhagic shock appears to be responsible for producing hepatocellular dysfunction possibly through the up-regulation of IL-6 and PGE2. In view of this, long-lasting hypoxemia in trauma victims should be avoided, perhaps by early intubation and ventilation so that the potential additional proinflammatory cytokine and PGE2 release can be prevented.
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PMID:Severe hypoxemia in the absence of blood loss depresses hepatocellular function and up-regulates IL-6 and PGE2. 924 88

Peritonitis remains a major problem in peritoneal dialysis. The incidence of peritonitis may be reduced by the use of more "biocompatible" peritoneal dialysis solutions that do not impair local host defense mechanisms, such as occurs with conventional lactate-buffered glucose solutions. In the present study, we investigated the use of bicarbonate and lactate as buffer systems and glucose, amino acids, and glucose polymer as osmotic agents on specific cellular functions of isolated fresh blood monocytes in vitro. The bicarbonate-buffered solutions had a physiologic pH (7.0 to 7.6). Lactate-buffered solutions were tested with a pH between 5.5 and 7.3. RPMI 1640 (Roswell Park Memorial Institute, supplied by Biochrom, Berlin, Germany) and phosphate-buffered saline were used as control mediums. The test solutions were incubated with 200,000 monocytes/mL for 45 minutes followed by a 1:1 mix with RPMI 1640 (with supplements) during a 24- or 4-hour tetrazolium bromide test (MTT test) recovery period. Constitutive and lipopolysaccharide (LPS)-stimulated release of interleukin-1beta (IL-1beta) and IL-6 in the supernatants as parameters of cellular host defense and lactate dehydrogenase concentrations and MTT-formazan production as parameters for cell cytotoxicity were measured. Significantly higher IL-6 and IL-1beta release was found in the bicarbonate-buffered solutions, both under basal conditions and after LPS stimulation, compared with the lactate-buffered solutions (LPS stimulation: 1% amino acids/34 mmol/L bicarbonate, IL-1beta: 1,166 +/- 192 pg/mL; 1.5% glucose/34 mmol/L bicarbonate, IL-1beta: 752 +/- 107 pg/mL; 1.5% glucose/35 mmol/L lactate/pH 5.5, IL-1beta: 174 +/- 51 pg/mL). Some of these differences could even be detected in spent dialysate after a 6-hour dwell in continuous ambulatory peritoneal dialysis patients (n = 10). A lower degree of cellular cytotoxicity (lactate dehydrogenase activity) and better-preserved metabolic activity (MTT test) also were found for the bicarbonate-buffered solutions. Amino acids (1%) proved to be comparable to glucose (1.5%) as an osmotic agent at a neutral pH with regard to LPS-stimulated cytokine release and cytotoxicity. The incubation with a glucose polymer solution (7.5% glucose polymer in phosphate-buffered saline, pH 7.3) resulted in a significantly lowered cytokine release (LPS stimulation: IL-1beta, 69 +/- 19 pg/mL) compared with the other solutions with neutral pH (P < 0.01). These results suggest that bicarbonate as a buffer provided better biocompatibility with regard to mononuclear cytokine release and viability compared with lactate. Amino acids and glucose were equivalent to these parameters at a physiologic pH. The glucose polymer solution, however, was associated with a marked depression of cytokine release.
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PMID:Osmotic agents and buffers in peritoneal dialysis solution: monocyte cytokine release and in vitro cytotoxicity. 929 71

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