Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using in situ immunohistochemistry and a specific monoclonal antibody (mcab R1G10), we analyzed the expression of the human interferon-gamma receptor (HuIFN-gamma R) and its topographical distribution in normal liver biopsies and in biopsies with various inflammatory liver diseases. In normal liver tissue, mcab R1G10 reacted weakly with sinusoidal and vascular endothelial cells, while hepatocytes were distinctly negative. In pathological conditions, mcab R1G10 produced membranous, cytoplasmic and/or perinuclear staining of hepatocytes, in a topographical distribution which varied according to the type of liver disease. In acute hepatitis, R1G10-positive hepatocytes were diffusely distributed throughout the liver parenchyma, and showed strong cytoplasmic, as well as membranous and perinuclear reactivity. In chronic persistent hepatitis, weak membranous staining was found on a number of scattered hepatocytes in acinar zone 1, with more pronounced expression on single hepatocytes in acinar zone 3. In chronic active hepatitis and in active cirrhosis, a diffuse weak membranous reactivity throughout the liver parenchyma was accompanied by enhanced R1G10 expression in areas of inflammation in acinar zone 1. With immunoelectronmicroscopy, R1G10 reactivity was found on the peripheral cell membrane and on the microvillous canalicular cell membrane of hepatocytes in a strikingly discontinuous manner. In the cytoplasm, the reaction product was detected on the cisternae of the rough endoplasmic reticulum and on small vesicles which were especially abundant in the perinuclear area. Our results demonstrate the absence of HuIFN-gamma R on hepatocytes in the normal liver, and its de novo expression during inflammatory liver disease. These findings indicate that hepatocytes, by displaying the HuIFN-gamma R, may act as target cells for the immunoregulatory action of IFN-gamma during liver inflammation.
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PMID:Expression of interferon-gamma receptor in normal and pathological human liver tissue. 182 21

A low-molecular-weight fraction (M.W. approximately 700) that specifically impairs the induction of type II interferon in mice by purified protein derivative of tuberculin or OK-432 was isolated from the cell-free ascitic fluid of mice bearing Ehrlich ascites carcinoma. Purification was achieved by ultrafiltration and gel filtration. The inhibitory activity of the isolated fraction was 10 times greater than that of the unfractionated starting material in the impairment of type II interferon induction. The significant inhibition was observed even when 0.2 ml of the 10,000-fold dilution of the fraction, which was previously adjusted to 0.25 A unit at 290 nm absorption, was once treated i.p. in normal mice 48 hr before challenge of type II interferon inducers. This fraction was stable to heating at 56 degrees for 60 min. The active component, however, did not affect the in vivo induction of type I interferon by polyriboinosinic-polyribocytidylic acid or tilorone-HCl. In parallel experiments, an identical low-molecular-weight fraction that impairs the type II interferon induction in mice was isolated from the ascitic fluids of rats bearing AH-100B ascites tumor and from a human hepatoma case with advanced cancer metastatic to the peritoneal cavity. However, nontumorous ascitic fluids obtained from adjuvant-stimulated mice and a human liver cirrhosis case did not contain any such inhibitory activity.
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PMID:Isolation of an inhibitor of type II interferon induction from tumor ascitic fluids. 624 7

The possible involvement of cell-mediated immune responses to liver-specific protein in the pathogenesis of liver injury was investigated. The subjects consisted of seven patients with acute hepatitis, 12 cases with chronic active hepatitis, four cases with chronic inactive hepatitis, and three cases with liver cirrhosis. When peripheral blood lymphocytes from these patients were cultured in the presence of liver specific protein, and lymphocyte transformation was determined by measuring the uptake of [3H]thymidine into acid-insoluble materials, positive blastogenesis was seen in two cases with acute hepatitis and in six cases with chronic active hepatitis. The macrophage activating factor (MAF), a kind of lymphokine, was also detectable in the culture medium of activated lymphocytes from six patients who showed positive blastogenesis by estimating [3H]glucosamine incorporation into macrophages. Furthermore, the MAF-activated macrophages wer shown to be cytotoxic for the isolated liver cells causing marked inhibition of albumin synthesis. This macrophage-mediated cytotoxicity was detected in eight cases that showed positive lymphocyte transformation. These observations suggest that macrophage-mediated cytotoxicity plays a role in the pathogenesis of chronic active hepatitis.
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PMID:Immunological studies on chronic active hepatitis: possible involvement of macrophage-mediated cytotoxicity in its immunopathogenesis. 704 38

Blood samples from 29 healthy individuals (control), 16 chronic alcohol abusers without clinical symptoms of liver disease, 22 patients with alcoholic steatosis and 31 patients with alcoholic cirrhosis were obtained. The antiviral activity, only partially neutralized by polyclonal and monoclonal anti-HuIFN-alpha and monoclonal anti-HuIFN-gamma antibodies, was detected in sera of 38% healthy controls and of 64-77% alcoholic abusers without or with ALD. To measure the activity of the IFN system, leukocyte cultures of chronic alcohol abusers and control individuals were set up using a whole blood technique. Common IFN inducers: NDV, PHA and ConA were used. Blood leukocytes of patients with alcoholic steatosis and cirrhosis responded to NDV, PHA and ConA with significantly lower IFN levels than controls, whereas IFN response of alcoholics without liver diseases was lower only after stimulation with ConA. Regarding the lymphoproliferative test performed with PHA, a remarkably diminished lymphocyte response of patients with cirrhosis was observed as compared to control. Our data indicate that long term ethanol intake impairs the ability of leukocytes and their subpopulation to produce IFNs. The correlation between ALD progression and the defect in IFN production suggests that suppressive action of ethanol, liver injury and immune reactions involved in liver damage may be responsible for impairment of the IFN system in heavy drinkers.
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PMID:Interferon production by peripheral blood cells of patients with alcoholic liver disease (ALD). 748 59

Cytokines constitute a complex network of molecules involved in the regulation of the inflammatory response and the homeostasis of organ functions. Cytokines coordinate physiologic and pathologic processes going on in the liver, such as liver growth and regeneration, inflammatory processes including viral liver disease, liver fibrosis and cirrhosis. Liver growth and regeneration are regulated by several cytokines. The platelet-derived hepatocyte growth factor, in particular, delivers a strong mitogenic stimulus for hepatocyte regeneration. The cell-mediated immune response plays a central role in hepatocellular necrosis and in the immunopathogenetic mechanisms involved in viral clearance and persistence in liver disease of viral etiology. In this context, cytokines modulate the immune system and exert direct antiviral activity by cytopathic and non-cytopathic mechanisms, as demonstrated in a transgenic mouse model. IL-6, TNF-alpha, IL-1 and IL-2 increase in acute fulminant viral hepatitis; in fact, they have pro-inflammatory and cytotoxic effects. Reduced IL-2 and IFN-alpha synthesis and increased serum levels of IL-1 and IL-2 soluble receptor (IL-2R) have been observed in HBV chronic liver disease. In HCV chronic hepatitis, IL-2R increases as well, while IFN-gamma and IL-2 decrease. In personal experimental observations, intra-hepatic messenger RNA expression of several cytokines was measured in liver specimens of patients with chronic HBV and HCV infections: patients with HCV chronic liver disease had higher levels of IL-2, IL-6, IL-10, and IFN-gamma. These data are in accordance with immunological studies showing a vigorous cell-mediated immune response in HCV chronic liver disease and a deficient immune response in HBV chronic hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Cytokine mediators in acute inflammation and chronic course of viral hepatitis]. 772 1

Cytokine response to viral infection can be of critical importance in the host defense against virus. Interferon (IFN)-gamma and interleukin (IL)-2 have wide ranges of activities in host defense mechanisms. Therefore, these cytokine genes in the liver were investigated in a series of patients with hepatitis C virus (HCV) infection using a reverse transcribed-polymerase chain reaction (RT-PCR). Total RNA was purified from liver biopsies, reverse transcribed to cDNA, amplified by specific primers, and the products were detected by agarose gel and slot blot hybridization. All samples from acute hepatitis (AH; n = 4) and chronic hepatitis patients (CH; n = 19) were positive for IFN-gamma at varying degrees. AH patients showed strong signals compared to CH patients, liver cirrhosis (LC; n = 12; 72% positive) patients, and hepatocellular carcinoma (HCC; n = 21; 19% positive) patients. IL-2 gene was undetectable in all patients tested. IL-2 receptor (IL-2R) was detectable in AH, CH and LC patients but not in HCC patients. We conclude that IFN-gamma has important roles in the cytokine network that indeed present in the liver of HCV patients while the presence of IL-2R gene may indicate that the signaling pathway for IL-2 is intact.
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PMID:Interferon-gamma, interleukin (IL)-2 and IL-2 receptor expressions in hepatitis C virus-infected liver. 839 42

An imbalance between T helper cell (Th)1 and Th2-like cytokines has been described in several chronic infectious diseases. We therefore analyzed the intrahepatic messenger RNA (mRNA) expression of Th1-like (interleukin [IL]-2, interferon [IFN]-gamma) and Th2-like (IL-4, IL-10) cytokines in chronic hepatitis C patients (n = 17) and controls (n = 6) and correlated the results with liver histology and intrahepatic viral load. Intrahepatic cytokine mRNA and hepatitis C virus (HCV) RNA were quantitatively assessed by polymerase chain reaction (PCR) using a dot-blot hybridization technique. Liver biopsy specimens were histologically graded using the Scheuer Score. IFN-gamma and IL-2 mRNA expression were significantly upregulated in chronic HCV vs. controls (P < .002, P < .04, respectively). Both correlated significantly with histological fibrosis and portal tract inflammation. In contrast, the expression of IL-10 mRNA was decreased in cirrhosis and chronic HCV compared with controls (P < .02, P < .0001, respectively). IL-4 mRNA was detected inconsistently at low levels in all groups. Intrahepatic viral load did not correlate with either cytokine expression or tissue injury. In conclusion, the progressive liver injury seen in chronic HCV is associated with the upregulation of intrahepatic Th1-like cytokines and the downregulation of IL-10, a Th2-like cytokine. These results suggest a role for delayed-type hypersensitivity immune reactions in HCV related liver injury.
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PMID:Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines. 885 73

No previous studies have been reported on human alcoholism in which the pattern of cytokine secretion by natural killer (NK) cells is explored. The goal of the present study was to evaluate the role of NK cells in the production of cytokines in patients with chronic alcoholism, analyzing at the same time the possible relationship between cytokine production and both alcoholic liver disease and ethanol (EtOH) intake. A total of 30 chronic alcoholic patients-11 without liver disease [alcoholics without liver disease (AWLD) group] and 19 diagnosed of alcoholic liver cirrhosis-were included in this study. Twenty-five age- and sex-matched healthy volunteers were analyzed as controls. Production of interferon (IFN)-gamma, tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6 was performed on NK-enriched peripheral blood mononuclear cells (PBMC) after stimulation with IL-2 and IFN-alpha. In AWLD patients, the production of TNF-alpha was significantly reduced, compared with normal controls, under both IFN-alpha (p < 0.01) and IL-2 (p < 0.05) stimulation. In patients with cirrhosis, TNF-alpha production by PBMC enriched in NK cells varied depending on the EtOH intake status at the moment of evaluation. Accordingly, an increased concentration of this cytokine was detected in the supernatants of cirrhotic patients and active EtOH intake, particularly after IFN-alpha stimulation (p < 0.05); whereas, in patients with at least 1 year of alcohol withdrawal, TNF-alpha levels remained within normal range. The results on the production of IL-6 and IFN-gamma in AWLD and cirrhotic patients showed that only cirrhotic patients with a prolonged EtOH withdrawal period display abnormal production. Accordingly, in this group of patients, a significantly increased release of IL-6 was observed after both IFN-alpha and IL-2 stimulation (p < 0.01 and p < 0.05, respectively). By contrast, a lower IFN-gamma production (p < 0.005) was detected with respect to the control group. Our results point to the existence of an abnormal cytokine secretion by NK cells from chronic alcoholism patients, which depend on both the existence of liver disease and the status of EtOH intake.
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PMID:Alterations in tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 production by natural killer cell-enriched peripheral blood mononuclear cells in chronic alcoholism: relationship with liver disease and ethanol intake. 934 83

The chronic alcoholic patient is usually immunosuppressed, but the significance of this phenomenon in terms of bile duct injury is unclear. The immunoreactivity of the bile duct cells was examined in a series of 69 frozen liver biopsy specimens obtained from patients with alcoholic liver disease, comprising 29 cases of cirrhosis, 26 of alcoholic hepatitis, 10 cases of alcoholic fatty liver, and 4 specimens from normal livers. Liver diseases such as primary biliary cirrhosis and human hepatic allograft rejection, known to have an autoimmune basis, share the characteristic feature of damage to the bile duct epithelial cells. In both instances the damage seems to be immune mediated, but the nature of the antigens involved is not established. We used the avidin-biotin-peroxidase complex method to test in alcoholic liver disease for the expression of a battery of surface antigen markers that have been incriminated in tissue injury and are usually present in lymphoid cells but also expressed by epithelium. In this study we investigated the expression of the following molecules: HLA class I (ABC) and class II (HLA-DR, HLA-DP, HLA-DQ), CD29, CD45RA, CD45RO, CD56, interleukin 1 (IL-I), IL-2, IL-4, interferon (IFN-gamma), tumor necrosis factor beta, and transforming growth factor beta1 (TGF-beta1). The bile duct epithelial cells strongly expressed HLA-ABC in all cases, CD56 in 47 of 55, IL-4 in 15 of 41, TGF-beta1 in 14 of 25, and CD29 in 4 of 25 cases. The other markers including IFN-gamma, HLA-DR, HLA-DP, and HLA-DQ were not expressed by bile duct cells. The expression of HLA class I agrees with previous observations while the absence of class II expression does not. The expression by the bile duct epithelium of CD56 confirms our own previous report. A new observation is the finding of molecules such as IL-4, TGF-beta1, and CD29 strongly expressed in the bile ducts cells. The presence of these molecules, taken together with the lack of IFN-gamma expression, contradicts previous speculations that attributed to IFN-gamma a role in the induction of major histocompatibility antigens and adhesion molecules in immune-mediated alcoholic liver disease.
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PMID:The antigenic heterogeneity of the bile duct epithelium in alcoholic liver disease. VA Cooperative Study Group 275. 1023 99

The role played by chemokines in regulating the selective recruitment of lymphocytes to different tissue compartments in disease is poorly characterized. In hepatitis C infection, inflammation confined to portal areas is associated with a less aggressive course, whereas T cell infiltration of the liver parenchyma is associated with progressive liver injury and cirrhosis. We propose a mechanism to explain how lymphocytes are recruited to hepatic lobules during bursts of necroinflammatory activity in chronic hepatitis C infection. We report here that lymphocytes infiltrating hepatitis C-infected liver express high levels of the chemokine receptors CCR5 and CXCR3. However, whereas the CCR5 ligands macrophage inflammatory protein-1alpha and -1beta were largely confined to vessels within portal tracts, the CXCR3 ligands IFN-inducible protein-10 and monokine-induced by IFN-gamma were selectively up-regulated on sinusoidal endothelium. In vitro, human hepatic sinusoidal endothelial cells secreted IFN-inducible protein-10 and monokine-induced by IFN-gamma in response to stimulation with IFN-gamma in combination with either IL-1 or TNF-alpha. This suggests that intrahepatic Th1 cytokines drive the increased expression of IFN-inducible protein-10 and monokine-induced by IFN-gamma and thereby promote the continuing recruitment of CXCR3-expressing T cells into the hepatic lobule in chronic hepatitis C infection.
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PMID:Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. 1057 Mar 16


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