Role of defective monocyte interleukin‐10 release in tumor necrosis factor‐alpha overproduction in alcoholic cirrhosis (original) (raw)
Related papers
Gut, 2000
Background-In patients with alcoholic liver cirrhosis, endotoxaemia is a frequent finding. Unknown mechanisms, however, prevent typical clinical symptoms of endotoxaemia in many patients. Methods-We determined plasma levels of pro-and anti-inflammatory mediators, ex vivo cytokine secretion capacity, and expression of tumour necrosis factor (TNF) receptors on phagocytic blood cells in 49 patients with alcoholic cirrhosis and 41 age matched healthy controls. Results-In addition to increased levels of proinflammatory cytokines in cirrhotic patients, we observed consistent upregulation of the anti-inflammatory mediators interleukin 10 (IL-10) (plasma 15.75 (1.6) v 6.6 (1.3) pg/ml (p<0.001); ex-vivo 108.4 (22.0) v 40.1 (7.4) pg/ml (p<0.05)), interleukin 1 receptor antagonist (plasma 527.1 (83) v 331.4 (56) pg/ml (p<0.05); ex vivo 19.9 (3.4) v 10.2 (2.7) ng/ml (p<0.01)), and soluble TNF receptors (sTNF-R) in plasma (sTNF-RI 3157.2 (506.2) v 607.9 (300.3) pg/ml; sTNF-RII 3331.0 (506.2) v 1066.4 (225.1) pg/ml (p<0.001 for both)). Desensitisation at the target cell level was indicated by reduced expression of TNF receptor I on granulocytes (64.8 (6.5) v 40.1 (7.3)% positive cells; p<0.05) and unaltered plasma levels of soluble E-selectin. Conclusion-In patients with alcoholic liver cirrhosis, upregulation of the proand anti-inflammatory cytokine system and simultaneous desensitisation of eVector cells could explain the restricted systemic inflammatory response to chronic endotoxaemia. This alteration in immune status may lead to impairment of host defences against infections which are frequent complications of alcoholic cirrhosis.
Balance between pro and anti-inflammatory cytokines in patients with acute alcoholic hepatitis
Gastroentérologie Clinique et Biologique, 2005
The ability of endogenous IL-10 to modulate inflammatory response and to limit hepatotoxicity has been shown in several models of liver injury. Aims-The objectives of this study were to evaluate the relationship between liver disease and the balance between pro and antiinflammatory cytokines in acute alcoholic hepatitis. Methods-Twenty-five patients with pure steatosis, 17 with cirrhosis and mild acute alcoholic hepatitis (discriminant function value < 32) and 41 patients with cirrhosis and severe acute alcoholic hepatitis (discriminant function value ≥ 32) were studied. Plasma levels of interleukin 10 (IL-10) and soluble TNF receptors (TNFsRp75 and 55) were analyzed using ELISA assays. Hepatocyte proliferative activity was assessed with proliferating cell nuclear antigen labeling index (PCNA-LI) on formalin-fixed paraffin embedded liver biopsy specimens. Results-In patients with steatosis, cirrhosis with mild and severe acute alcoholic hepatitis, the plasma levels of IL-10 were higher (P < 0.05) than in healthy controls. Between day 1 and day 8, the TNFsRp55/IL-10 ratio increased by 137 ± 47 in the 10 patients with severe acute alcoholic hepatitis treated with prednisolone who died within 2 months and by 9.3 ± 14 in the 19 patients still alive at 2 months (P = 0.031). In patients with severe acute alcoholic hepatitis, PCNA-LI on liver biopsy was negatively correlated with the TNFsRp55/IL-10 ratio increase from day 1 to day 8 (r =-0.42, P = 0.11). PCNA-LI was positively correlated with TNFsRp75/TNFsRp 55 ratio increase from day 1 to day 15 (r = 0.52; p < 0.05). Conclusion-Our data suggest the anti-inflammatory system is upregulated in patients with alcoholic liver disease. Nevertheless, in patients with severe acute alcoholic hepatitis, IL-10 production seems insufficient to modulate TNF-α cytotoxicity mediated by TNFRp55.
Increased cytokine production is associated with acute inflammation in cirrhotic alcoholic patients
International Hepatology Communications, 1997
The role of cytokines in the etiology of liver injury and their contribution to the systemic manifestations that occur in patients with liver disease, are not clearly understood. Aim: To study if serum levels and in vitro blood mononuclear cell (BMC) production of IL-I/Y and TNFcr are related to the severity of alcoholic liver cirrhosis, and identify potential factors that can modify cytokine production in these patients. Serum levels, spontaneous and in vitro LPS stimulated BMC production of Interleukin-Ifi (IL-I/3) and Tumor Necrosis Factor a (TNFc(), were measured in 38 patients with alcoholic cirrhosis Child B or C, and nine normal volunteers. Serum levels and spontaneous in vitro production of IL-Ip and TNFcl were below detection limits. There were no differences between normal controls and Child B or C patients in LPS-stimulated production of IL-Ia or TNFcr. However eight patients with alcoholic hepatitis or infections superimposed on cirrhosis, had higher levels on LPSstimulated BMC production of IL-I/I (12.9 f 5.8 rig/ml) and TNFcr (4.9 f 2.3 rig/ml) than the rest of cirrhotic patients (5.3 k 3.5 and 1.8 + 0.9 rig/ml). There was no association between IL-Ifi and TNFcl BMC production and parameters of liver function or recent alcohol ingestion. Increased levels of IL-I/r' and TNFa production by stimulated BMC are associated with acute inflammatory events in cirrhotic alcoholic patients and not with the severity of liver disease. 0 1997 Elsevier Science Ireland Ltd.
Relation of Lymphocyte Subsets and Cytokines in Different Grades of Alcoholic Cirrhosis
JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH, 2019
Introduction: The pathogenesis of Alcoholic Liver Disease (ALD) shows immune dysregulation with decreasing lymphocyte subsets and increasing CD4/CD8 ratio. T lymphocyte activation leads to secretion of cytokines like Tumour Necrosis Factor-a (TNF-a) and interleukins causing inflammation and fibrosis. Aim: To correlate lymphocyte subsets and TNF-a and Interleukin 6 (IL-6) in different grades of alcoholic cirrhosis.
Journal of Hepatology, 2004
To investigate the distribution and activation state of circulating monocytes and T-cell subsets, their contribution to tumour necrosis factor-alpha (TNFα) production, and their potential relationship with bacterial products of enteric origin in alcoholic cirrhosis.Peripheral blood monocytes and T-lymphocytes from 60 cirrhotic patients and 24 controls were characterized by four-color flow-cytometry after labelling of differentiation antigens and cytokines, before and after a 4-week course of norfloxacin or placebo.Monocytes from ascitic patients showed increased number, enhanced CD80 and HLA-DR surface levels, and spontaneous intracytoplasmic TNFα expression, when compared to non-ascitic patients and controls. Blood TNFα levels directly correlated with the amount of TNFα expressed by monocytes. In ascitic patients, there was a collapse of virgin CD4+ and CD8+ T-cell subsets; and, an expansion of activated CD4+ T-cells. The above abnormalities were mainly restricted to ascitic patients with high serum levels of lypolysaccharide-binding-protein. Norfloxacin normalized the number of monocytes, reduced their activated phenotype and ability to produce TNFα and improved the abnormal T-cell homeostasis.In ascitic cirrhosis with high lipolysaccharide-binding-protein, monocytes are spontaneously activated to produce TNFα and are major contributors to the elevated serum TNFα. The T-cell compartment is profoundly depleted. Enteric bacterial products play a relevant role in these immune cellular abnormalities.
The Effect of Inflammatory Cytokines in Alcoholic Liver Disease
Mediators of Inflammation, 2013
Alcohol is the most common cause of liver disease in the world. Chronic alcohol consumption leads to hepatocellular injury and liver inflammation. Inflammatory cytokines, such as TNF-and IFN-, induce liver injury in the rat model of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as IL-6, and anti-inflammatory cytokines, such as IL-10, are also associated with ALD. IL-6 improves ALD via activation of the signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via activation of STAT3 in Kupffer cells and the subsequent inhibition of liver inflammation. Alcohol consumption promotes liver inflammation by increasing translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells through the LPS/Toll-like receptor (TLR) 4 pathways. Oxidative stress and microflora products are also associated with ALD. Interactions between pro-and anti-inflammatory cytokines and other cytokines and chemokines are likely to play important roles in the development of ALD. The present study aims to conduct a systemic review of ALD from the aspect of inflammation.
Cytokine levels in acute alcoholic hepatitis: a sequential study
Drug and Alcohol Dependence, 1995
Chronic alcoholic liver disease is associated with several immunological alterations: depressed T-cell function, low serum yinterferon, and high serum tumour necrosis factor (TNF-or) and interleukin levels. Therefore, macrophage activity seems to be enhanced. Some cytokines, such as TNF-(r, exert adverse effects on chronic alcoholic liver disease, so that protracted activation of macrophages with continuous TNF-or production may aggravate alcoholic hepatitis. Based on these facts we have sequentially determined serum levels of TNF-a, 18 interleukin (IL-l& y-interferon and neopterin-a macrophage product-at admission, and at the end of the first, third and sixth weeks after admission, of 43 patients affected by alcoholic hepatitis, and of 20 agematched sanitary workers as controls. Our patients showed higher levels of neopterin and lower levels of IL-lb and y-interferon than the controls; TNF-cx levels in our patients were almost significantly higher than in controls. TNF-ar levels at admission were higher in the patients who died (P = 0.025). TNF-ar and neopterin levels showed no trend to normalization in patients who died, with higher levels of neopterin at first and third weeks and higher TNF-(w and y-interferon levels at first week. Using logistic regression analysis, serum TNF-a! levels at admission showed significant (P = 0.045), independent effects on mortality, as well as serum neopterin (P = 0.0026) at the first week. Thus, enhanced macrophage activity, measured by serum levels of TNF-(r and neopterin seems to be related to a worse prognosis in alcoholic hepatitis.
Tumor Necrosis Factor and Alcoholic Liver Disease
Alcoholism: Clinical and Experimental Research, 1998
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 NFKB sensitizes to TNFinduced 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.
A Role for Interleukin-10 in Alcohol-Induced Liver Sensitization to Bacterial Lipopolysaccharide
Alcoholism: Clinical and Experimental Research, 2002
Background: Proinflammatory cytokines play an important role in alcohol-induced liver injury. The role of anti-inflammatory cytokines in the initiation and progression of alcoholic liver disease has received little attention. This study tested the hypothesis that an imbalance exists between pro-and anti-inflammatory cytokines in the liver during chronic exposure to alcohol. Alcohol exposure results in predominantly proinflammatory cytokine secretion and liver injury.
Alcoholic Liver Disease: Role of Cytokines
Biomolecules, 2015
The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor that contributes to the pathogenesis of ALD is lipopolysaccharide (LPS), which plays a central role in the induction of steatosis, inflammation, and fibrosis in the liver. LPS derived from the intestinal microbiota enters the portal circulation, and is recognized by macrophages (Kupffer cells) and hepatocytes. In individuals with ALD, excessive levels of LPS in the liver affect immune, parenchymal, and non-immune cells, which in turn release various inflammatory cytokines and recruit neutrophils and other inflammatory cells. In this review, we elucidate the mechanisms by which alcohol contributes to the activation of Kupffer cells and the inflammatory cascade. The role of the stellate cells in fibrogenesis is also discussed.