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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6 (hepatocyte stimulating factor) is a 26 kd cytokine that plays a major role in the acute phase response, especially the hepatic aspects of the acute phase response. Patients with alcoholic hepatitis manifest many aspects of the acute phase response. In this 6-month study we evaluated serial plasma interleukin-6 levels in 30 consecutive patients with moderate to severe alcoholic hepatitis. Mean admission plasma interleukin-6 activity was markedly increased (49.8 +/- 8.5 U/ml, normal less than 5 U/ml) in patients with alcoholic hepatitis, and levels decreased with clinical improvement to 15.6 +/- 6.1 U/ml at 6 months. Admission interleukin-6 activity correlated significantly (r = 0.82) with the severity of liver disease as assessed by the discriminant function of Maddrey. Also measured were selected assays postulated to be regulated by interleukin-6, including serum albumin (2.3 +/- 0.1 gm/dl), which was significantly depressed; alpha 1-acid glycoprotein (52 +/- 5 mg/dl), which was within normal limits; and IgA (827 +/- 70 mg/dl) and C-reactive protein (3.03 +/- 0.51 mg/dl), which were significantly elevated. Interleukin-6 activity fell over time in a pattern similar to that of bilirubin and C-reactive protein. We suggest that plasma interleukin-6 may not only regulate many aspects of the acute phase response but also may be a marker of inflammation and severity of disease in alcoholic hepatitis.
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PMID:Increased plasma interleukin-6 concentrations in alcoholic hepatitis. 158 11

Although altered cytokine homeostasis has been implicated in the pathogenesis of alcoholic liver disease, the relationship between cytokines and metabolic consequences of alcoholic liver disease is unknown. We, therefore, sought to correlate circulating concentrations of tumor necrosis factor-alpha, interleukin-1 and interleukin-6 to clinical and biochemical parameters of liver disease in chronic alcoholic patients. We used an enzyme-linked immunosorbent assay to measure plasma tumor necrosis factor and interleukin-1 and a bioassay to measure serum interleukin-6 in three groups of alcoholic men as follows: (a) actively drinking alcoholic men without evidence of chronic liver disease, (b) nondrinking alcoholic men with stable cirrhosis and (c) patients with acute alcoholic hepatitis. Mean cytokine concentrations were elevated in cirrhotic patients and alcoholic hepatitis patients compared with controls and alcoholic patients without liver disease. Tumor necrosis factor-alpha and interleukin-1 alpha concentrations remained elevated for up to 6 mo after diagnosis of alcoholic hepatitis, whereas interleukin-6 normalized in parallel with clinical recovery. Concentrations of all three cytokines were correlated with biochemical parameters of liver injury and hepatic protein synthesis plus serum immunoglobulin concentrations. We could not demonstrate a relationship between cytokine concentrations and peripheral endotoxemia. Percentages of peripheral blood monocytes that reacted with monoclonal antibodies to CD25 (interleukin-2 receptor) and human lymphocyte antigen-DR were similar for alcoholic patients and controls. These data suggest that tumor necrosis factor-alpha and interleukin-1 alpha are related to some of the metabolic consequences of both acute and chronic alcohol-induced liver disease, whereas interleukin-6 is related to abnormalities seen in acute liver injury.
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PMID:Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. 199 37

Recent studies in alcoholic hepatitis have proposed a role for the cytokine tumour necrosis factor-alpha (TNF-alpha) a mediator of endotoxic shock in sepsis. In this study plasma levels of the closely related cytokine interleukin-6 (IL-6) were assayed in 96 samples from 58 patients with severe alcoholic hepatitis, and 69 patients in control groups (21 normal, 10 alcoholic without liver disease, 10 inactive alcoholic cirrhosis, 18 chronic liver disease, 10 chronic renal failure). Plasma IL-6 levels were markedly elevated in patients with alcoholic hepatitis when compared with all control groups (P less than 0.001). IL-6 levels were higher in patients who died (P = 0.04) and correlated with the features of severe disease including: increased grade of encephalopathy, increased neutrophil count, increased prothrombin ratio, hypotension, increased serum creatinine and increased serum bilirubin. Surprisingly, no correlation was found between levels of plasma IL-6 and plasma TNF-alpha or endotoxin, or the presence of infection; an inverse correlation was found between plasma IL-6 and serum globulins. These findings provide further evidence that the IL-6/TNF cytokine system is activated in severe alcoholic hepatitis and may mediate hepatic or extra-hepatic tissue damage.
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PMID:Elevated plasma interleukin-6 and increased severity and mortality in alcoholic hepatitis. 204 24

Acute alcoholic hepatitis is accompanied by features of the acute phase response, peripheral blood neutrophilia and liver neutrophil infiltrate even in the absence of demonstrable bacterial or fungal infection. Plasma levels of tumour necrosis factor (TNF) and interleukin-6 (IL-6), the major cytokine inducers of the acute phase response, are markedly raised in acute alcoholic hepatitis and correlate closely with clinical and laboratory indicators of disease severity. The potent neutrophil activator and chemotaxin interleukin-8 (IL-8) is released in response to TNF and recent interest has focussed on its possible role in producing the characteristic peripheral blood neutrophilia and liver neutrophil infiltrate in alcoholic hepatitis. Circulating IL-8 and liver tissue levels of IL-8 are markedly raised in alcoholic hepatitis, with highest levels in patients who die within the first four weeks of admission to hospital. There is a close correlation between hepatic IL-8 and infiltration with neutrophils. Less dramatic increases in circulating IL-8 are present in abstinent alcoholic cirrhotics and patients admitted for detoxification. These observations suggest a central role for IL-8 in the neutrophilia and hepatic neutrophil infiltrate characteristic of acute alcoholic hepatitis.
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PMID:Interleukin-8 in alcoholic liver disease. 781 Feb 74

Plasma levels of endotoxin and tumor necrosis factor alpha (TNF alpha) and the cytokine response of isolated monocytes were examined in chronic alcohol abusers with various degrees of liver disease. In 35 patients - 19 with alcoholic fatty liver (AF), 7 with alcoholic hepatitis (AH), 9 with cirrhosis (AC) - and in 15 healthy controls (HC), plasma levels of endotoxin were measured in the limulus assay, and plasma TNF alpha in an immunoassay. The cytokine response of monocytes stimulated in vitro with low doses of endotoxin (range: 25 pg/ml to 2.5 ng/ml) was determined in a cytolytic TNF bioassay and in TNF alpha and interleukin-6 (IL-6) immunoassays. All patient groups had elevated plasma endotoxin levels, whereas plasma TNF alpha was elevated only in AC (43.1 +/- 15.2 vs. HC: 5.0 +/- 1.1 pg/ml). Monocytes from all patient groups released increased amounts of bioactive TNF: AF 5.39 +/- 1.70, AH 7.10 +/- 3.28, AC 2.44 +/- 0.54 vs. HC 1.21 +/- 0.30 ng/ml (stimulation with 2.5 ng/ml endotoxin over 3 hrs.). Similar results were obtained in the TNF alpha immunoassay. Increased release of IL-6 from monocytes was shown only for AF, while values in AC were comparable to those in HC. These data confirm that endotoxemia is frequent in chronic alcoholics. In concert with an increased cytokine response of the monocyte/macrophage system, endotoxemia might contribute to the pathogenesis of alcoholic liver disease.
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PMID:Tumor-necrosis-factor and interleukin-6 response of peripheral blood monocytes to low concentrations of lipopolysaccharide in patients with alcoholic liver disease. 852 52

Patients with alcoholic hepatitis have several manifestations of the acute phase response (APR) and have elevated blood levels of interleukin-1, interleukin-6 and tumor necrosis factor-alpha. We have previously shown that liver stellate cells express interleukin-6 mRNA and protein and respond to this cytokine with increased expression of alpha1(I) procollagen mRNA. We further showed that the production of an APR episode stimulates a transient expression of alpha1(I) procollagen mRNA in the liver. In this communication we demonstrate that the concomitant induction of a weekly APR episode in rats with a schedule of CCl4 to produce cirrhosis, accelerates the development of liver fibrosis. We show that the enhancement of liver fibrosis is due, in part, to further upregulation in the expression of alpha1(I) procollagen and tissue inhibitor of metalloproteinases-1 mRNAs above values observed in control rats receiving only CCl4. The effect of the APR appears to have specificity since not all the mRNAs measured were equally affected. Altogether, these results suggest that increased blood or liver levels of APR cytokines, whether induced by APR episodes, endotoxin or other unrelated causes, may contribute to the development of liver fibrosis by enhancing the expression of type I collagen and of tissue inhibitor of metalloproteinases-1 mRNAs.
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PMID:Accelerated development of liver fibrosis in CCl4-treated rats by the weekly induction of acute phase response episodes: upregulation of alpha1(I) procollagen and tissue inhibitor of metalloproteinase-1 mRNAs. 930 Jul 99

Increased levels of hepatic and serum tumor necrosis factor (TNF) have been documented in animal models of alcoholic liver disease and in human alcoholic liver disease. This dysregulated TNF metabolism has been postulated to play a role in many of the metabolic complications and the liver injury of alcoholic liver disease. One potential therapy for alcoholic liver disease may be agents that downregulate TNF production or block TNF activity. Indeed, agents such as prostaglandins and glucocorticoids (both inhibit TNF production) have been used in both human liver disease and experimental models of liver injury, and anti-TNF antibody has recently been shown to attenuate the hepatotoxicity in an animal model of alcoholic-related liver disease. In this study, we demonstrate that a simple ex vivo system can be used to initially assess potential efficacy of anticytokine agents when administered to humans. Both prednisone and a prostaglandin analog were effective in downregulating TNF and interleukin-8 production. The liver is normally resistant to TNF cytotoxicity. Sensitivity to TNF cytotoxicity is thought to occur when there is inadequate production of hepatic protective factors. In this study, we showed that, when patients with acute alcoholic hepatitis were matched with trauma patients for serum levels of interleukin-6, they had similar depressions in the negative acute phase protein, albumin, but markedly different increases in the major acute phase protein, C reactive protein. Patients with alcoholic hepatitis had a very blunted response. We also showed that inhibiting activation of the redox sensitive transcription factor NFkappaB sensitizes to TNF-induced hepatocyte death in vitro. This transcription factor is important for the production of both cytokines and many acute phase protective factors. Several hepatic protective factors are induced by TNF. One possible mechanism for liver injury in alcoholic hepatitis may be inadequate generation of hepatic protective factors. Our future understanding of mechanisms of alcoholic liver disease will involve understanding the balance between noxious and protective factors in the liver, and this should lead to rational therapy for this disease process.
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PMID:Tumor necrosis factor and alcoholic liver disease. 972 45

The purpose of this study was to evaluate the role of the sinusoidal endothelial cell (SEC) during the clinical course of alcoholic hepatitis. Twenty consenting patients (mean age: 49.4 +/- 11.0 years) with moderate or severe hepatitis were studied. The patients were selected and characterized according to their history of drinking and laboratory profile, including serum aminotransferases, bilirubin, total white blood cell and neutrophil count, and prothrombin times. C-reactive protein and interleukin-6 were also measured as markers of the hepatic acute phase response. A marker of the SEC functional state, the circulating level of hyaluronan, was measured in parallel with the circulating levels of soluble intercellular adhesion molecule (sICAM)-1 over a 6-month observation period. All patients were hospitalized for the first month and encouraged to abstain from drinking for the duration of the study. The initial increased levels of both hyaluronan (542 +/- 32 ng x ml(-1) serum) and sICAM-1 (488 +/- 70 ng x ml(-1) serum), gradually fell during the 6-month observation period, eventually reaching values close to those seen in healthy subjects. A positive correlation was obtained between changes in these two markers of SEC function/activation on the one hand, and between these two tests and bilirubin, on the other hand. These data indicate that abnormalities of SEC function/activation, as reflected by serum hyaluronan and siCAM-1, are prominent in alcoholic hepatitis, and these alterations improve within relatively short periods of time after cessation of alcohol consumption.
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PMID:Hyperhyaluronanemia in alcoholic hepatitis is associated with increased levels of circulating soluble intercellular adhesion molecule-1. 975 49

Elevated concentrations of plasma proinflammatory cytokines have been detected in patients with alcoholic hepatitis (AH) and in a model of lipopolysaccharide-induced hepatitis in ethanol-fed Wistar rats. These cytokines have been implicated in the pathogenesis of the liver damage. Considering the likely involvement of the immune system in AH, and the frequent use of Lewis rats in autoimmune disease models, Lewis rats were examined in the model to determine whether they would more closely mimic the immune status of a chronic alcoholic and be a preferable strain for use in future experiments. Lipopolysaccharide-induced hepatic tumor necrosis factor-alpha, interleukin-1alpha, interleukin-1beta, and interleukin-6 mRNA expression was examined in both rat strains. The overall pattern of histological (panlobular piecemeal necrosis) and biochemical liver damage (plasma ALT levels), and cytokine expression was similar in both strains. Thus, it would appear that, despite the known susceptibility of Lewis rats to autoimmune phenomena, they do not respond to the experimental regime significantly better than Wistar rats. This study confirms that unknown mediators are contributing to the liver damage seen in this model and possibly in AH.
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PMID:A comparison of lipopolysaccharide-induced hepatitis in ethanol-fed Wistar and Lewis rats. 980 38

Both clinical findings and results of experiments with animal models of alcoholic hepatitis have shown the importance of cytokine-mediated cell-cell interactions in the onset of ethanol-induced liver damage. Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta (IL-1 beta), and interleukin-6, are released from Kupffer cells or infiltrating neutrophils and macrophages and elicit defensive responses in parenchymal cells, including activation of apoptosis. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), generated in response to cytokine-induced stress signals in parenchymal cells and also by activation of Kupffer cells and inflammatory cells, further mobilize cellular defense mechanisms. When these defensive responses are overwhelmed cells may die by necrosis, further stimulating inflammatory responses and infiltration of neutrophils. Chronic ethanol intake (i.e., many years of heavy alcohol use in human patients, several weeks or months in experimental animals) enhances the damaging consequences of these events through a variety of mechanisms. The formation of cytokines in the liver is stimulated by increasing circulating levels of endotoxin and by enhancing the responsiveness of Kupffer cells to such stimuli. In addition, ethanol promotes oxidative stress, both by increased formation of ROS and by depletion of oxidative defenses in the cell. Furthermore, liver cells from ethanol-treated animals are more susceptible to the cytotoxic effects of TNF-alpha and other cytokines than cells from control animals. Mitochondria play a critical role in the apoptotic response, and alterations in mitochondrial function after chronic ethanol treatment may contribute to enhanced cell death by apoptosis or necrosis. How the shift in the balance of cytokine-induced defensive and damage responses in hepatocytes contributes to the liver injury that occurs in alcoholic hepatitis remains poorly characterized and should be a rewarding area for future studies.
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PMID:Ethanol, oxidative stress, and cytokine-induced liver cell injury. 1206 39


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