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

The occurrence of antibodies to interferon-alpha 2a (anti-IFN-alpha 2a) to recombinant human IFN-alpha 2a was examined in chronic liver disease by a sensitive enzyme-linked immunosorbent assay (ELISA). Naturally occurring IgG and/or IgM anti-IFN-alpha 2a were found in one of 12 cases of chronic persistent hepatitis, four of 18 cases of chronic active hepatitis (CAH), two of 12 cases of liver cirrhosis, six of seven cases of primary biliary cirrhosis, nine of 11 cases of auto-immune CAH and none of 21 normal control subjects. Fifteen patients with viral CAH were treated with recombinant IFN-alpha 2a. Two of them were positive prior to receipt of IFN-alpha 2a and their titres increased after the therapy. Two patients became positive for anti-IFN-alpha 2a after the therapy. Absorption experiments revealed that anti-IFN-alpha 2a cross-reacted with native human leucocyte IFN-alpha and recombinant IFN-alpha 2b but not with recombinant IFN-beta and -gamma. The immunoblotting experiment confirmed the binding of antibodies to IFN. The results of anti-IFN-alpha 2a obtained by antiviral, cytopathic effect assay were in good agreement with those of IgG anti-IFN-alpha 2a, but not with those of IgM antibodies obtained by the ELISA. The ELISA described in the present study is a simple, sensitive and quantitative assay for anti-IFN-alpha 2a. It should be useful in assessing sub-specificities of anti-IFN and provide valuable information to predict the effect of IFN therapy and to elucidate the immunological abnormality in liver disease.
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PMID:Detection of anti-interferon-alpha 2a antibodies in chronic liver disease. 249 Dec 7

Interferon-gamma (IFN-gamma) was induced from a human peripheral mononuclear fraction by incubation with a streptococcal preparation stabilized with penicillin G (OK432). This IFN-gamma-producing activity was significantly reduced in patients with chronic hepatitis and hepatocellular carcinoma. In patients with liver cirrhosis it was also reduced but not significantly. Serum hepatitis B virus DNA and skin tests for the purified protein derivative of tuberculin, phytohemagglutinin-P and a polysaccharide fraction prepared from streptococcus pyogenes Su strain were determined to have no significant relation to this IFN-gamma-producing activity. Although the addition of interleukin 2 (IL-2) to the culture medium enhanced the IFN-gamma-producing activity, there was no difference in this enhancement between normal control and chronic hepatitis. Therefore reduction of the IFN-gamma-producing activity observed in chronic hepatitis seems to be caused by a decreased number of IFN-gamma-producing activity cells or hypofunction of these cells or both. Since HBeAg became negative in patients whose IFN-gamma-producing activity was increased by the administration of the immunopotentiator OK432 or IFN-beta, the IFN-producing system in the patients with B type hepatitis may contribute to the elimination of HBV. Adenine arabinoside suppressed IFN-gamma-producing activity both in vivo and in vitro.
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PMID:In vitro interferon producing activity of peripheral mononuclear cells in patients with chronic liver disease. 303 38

A monoclonal antibody to human interferon-alpha (IFN-alpha) was produced using affinity-purified IFN-alpha, that reacted with recombinant human IFN-alpha 2, but not with IFN-alpha 1, IFN-alpha M1 or IFN-beta. Indirect immunofluorescence using this monoclonal (designated 6C3) and anti-IFN-alpha polyclonal antibodies identified cells expressing IFN-alpha. After Sendai virus induction of normal human buffy-coat cells the proportion of monocytes and lymphocytes expressing IFN-alpha rose progressively from 0% to 50% and 34% respectively, preceding peak IFN-alpha titres in the culture supernatants. Around 80-90% of polymorphs were IFN-alpha-positive using both antisera, with or without IFN induction, although very little IFN bioactivity was released to the supernatant of polymorph cultures after IFN induction. Sections of hepatitis B virus infected human liver tissue showed foci of IFN-alpha-positive infiltrating mononuclear cells and (to a lesser extent) fibroblasts in patients who had active cirrhosis and evidence of virus replication. These findings suggest that polymorphs constitutively express IFN-alpha 2 related antigenic activity, whose biological activity is at present unknown; and demonstrates the identification of IFN-alpha-expressing cells in sections of tissue undergoing natural virus infection.
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PMID:Production of a monoclonal antibody to human interferon-alpha (IFN-alpha) and its use to identify IFN-alpha-producing cells in virus infection in vivo. 350 87

Histological progress is one of the predictors of an unfavourable response to interferon (IFN) therapy in hepatitis C virus (HCV)-associated chronic liver diseases (CLD). The aim of the present study was to investigate whether histological progress has an association with the expression of IFN receptor (IFN-Rc) in the liver. Expression of mRNA of the IFN-Rc for IFN-alpha was investigated by reverse transcription polymerase chain reaction using liver biopsy specimens from 37 HCV-associated CLD comprising 11 liver cirrhosis (LC) and 26 chronic hepatitis (CH) cases. IFN-alpha and IFN-beta mRNA were detected in over 90% of subjects. In contrast, the detection rate of IFN-Rc mRNA in chronic persistent hepatitis, chronic hepatitis 2A, chronic hepatitis 2B and liver cirrhosis (LC) was 100, 71.4, 22.2 and 0%, respectively. The absence of IFN-Rc mRNA was significantly associated with the severity of fibrosis of the liver. These results indicated that IFN-Rc expression decreases with the histological progress of the disease, suggesting that lower expression of IFN-Rc mRNA may be partially responsible for the poor IFN response in LC.
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PMID:Relationship between the intrahepatic expression of interferon-alpha receptor mRNA and the histological progress of hepatitis C virus-associated chronic liver diseases. 887 66

Because hepatocellular carcinoma often recurs after surgical resection or ethanol injection therapy, we conducted a prospective randomized controlled trial of interferon (IFN) in patients with chronic liver disease caused by hepatitis C virus (HCV). Twenty eligible patients with cirrhosis were randomized into two groups: 10 patients treated with 6 million units of natural IFN-beta twice a week for 36 months and 10 patients without IFN therapy. One patient within the treatment group discontinued interferon therapy after 19 months of treatment because of a mild degree of retinopathy. None of the patients in either group lost HCV-RNA until the end of the observation. Although 7 (70.0%) of 10 patients in the nontreatment group showed tumor recurrence, only 1 (10.0%) of 10 patients with IFN therapy developed tumor recurrence during a median observation period of 25.0 months. Cumulative recurrence rates of the treated and untreated groups were 0% and 62.5% at the end of the first year, and 0% and 100% at the second year, respectively (log-rank test, P =.0004). In conclusion, intermittent administration of IFN suppressed tumor recurrence after treatment with surgery or ethanol injection in patients with HCV-related chronic liver disease.
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PMID:Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer. 1117 57

Treatment approaches with recombinant IFN-alpha2b and natural IFN-beta in a patient with chronic hepatitis C (genotype 1b) and cirrhosis had, in both cases, to be terminated prematurely due to breakthrough phenomena and thrombo-leukocytopenia up to WHO grade 3. After the patient was switched to highly purified natural IFN-alpha (Multiferon) the thrombocyte and leukocyte counts increased significantly, and sustained complete biochemical and virological response could be achieved.
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PMID:Successful long-term application of highly purified natural interferon-alpha (multiferon) after preceding interferon approaches in a chronic hepatitis C patient with thrombocytopenia. 1528 92

Innate cellular antiviral defenses are likely to influence the outcome of infections by many human viruses, including hepatitis B and C viruses, agents that frequently establish persistent infection leading to chronic hepatitis, cirrhosis, and liver cancer. However, little is known of the pathways by which hepatocytes, the cell type within which these hepatitis agents replicate, sense infection, and initiate protective responses. We show that cultured hepatoma cells, including Huh7 cells, do not activate the interferon (IFN)-beta promoter in response to extracellular poly(I-C). In contrast, the addition of poly(I-C) to culture media activates the IFN-beta promoter and results in robust expression of IFN-stimulated genes (ISG) in PH5CH8 cells, which are derived from non-neoplastic hepatocytes transformed with large T antigen. Small interfering RNA knockdown of TLR3 or its adaptor, Toll-interleukin-1 receptor domain-containing adaptor inducing IFN-beta (TRIF), blocked extracellular poly(I-C) signaling in PH5CH8 cells, whereas poly(I-C) responsiveness could be conferred on Huh7 hepatoma cells by ectopic expression of Toll-like receptor 3 (TLR3). In contrast to poly(I-C), both cell types signal the presence of Sendai virus infection through a TLR3-independent intracellular pathway requiring expression of retinoic acid-inducible gene I (RIG-I), a putative cellular RNA helicase. Silencing of RIG-I expression impaired only the response to Sendai virus and not extracellular poly(I-C). We conclude that hepatocytes contain two distinct antiviral signaling pathways leading to expression of type I IFNs, one dependent upon TLR3 and the other dependent on RIG-I, with little cross-talk between these pathways.
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PMID:Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes. 1573 93

Type I interferons (IFNs), IFN-alpha and IFN-beta, are widely used for treating chronic hepatitis C. Although retrospective studies have suggested that type I IFNs have direct antifibrotic effects, little is known about these mechanisms. The present study was designed to clarify the preventive mechanisms of type I IFNs in the progression of fibrosis for the establishment of a more effective therapy. A murine fibrosis model comprising immunological reactions was induced by the administration of concanavalin A (0.3 mg/body) into mice once a week for 4 weeks. Liver injury and the degree of fibrosis were determined by measuring the serum alanine aminotransferase activities and liver hydroxyproline contents with or without IFN-beta pretreatment. IFN-beta suppressed the hepatocellular injury and increased the hydroxyproline content induced by repeated concanavalin A injections, but had no effect on established fibrosis. Furthermore, IFN-beta reduced the expressions of transforming growth factor-beta, basic fibroblast growth factor, collagen type I A2 and tissue inhibitor of metalloproteinase 1 messenger RNAs, which are related to the progression of liver fibrosis. The IFN-beta reduced the liver injury and fibrosis induced by immunological reactions. These data suggest that type I IFNs suppress the progression of cirrhosis through inhibition of repeated hepatocellular injury and/or factors that promote the liver fibrosis induced by hepatitis virus infection.
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PMID:Interferon-beta reduces the mouse liver fibrosis induced by repeated administration of concanavalin A via the direct and indirect effects. 1764 99

Chronic ethanol (EtOH) abuse results in the development of steatosis, alcoholic hepatitis, and cirrhosis. Augmented TNF-alpha production by macrophages and Kupffer cells and signaling via the p55 TNF receptor have been shown to be critical for these effects of chronic EtOH; however, the molecular mechanisms leading to augmented TNF-alpha production remain unclear. Using cell culture models and in vivo studies we demonstrate that chronic EtOH results in increased TNF-alpha transcription, which is independent of NF-kappaB. Using reporter assays and chromatin immunoprecipitation we found that this increased transcription is due to increased IRF-3 binding to and transactivation of the TNF promoter. As IRF-3 is downstream from the TLR4 adaptor TIR-domain-containing adapter-inducing IFN-beta (Trif), we demonstrate that macrophages from Trif-/- mice are resistant to this dysregulation of TNF-alpha transcription by EtOH in vitro as well as EtOH-induced steatosis and TNF dysregulation in vivo. These data demonstrate that the Trif/IRF-3 pathway is a target to ameliorate liver dysfunction associated with chronic EtOH.
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PMID:TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol. 1871 75

Hepatitis C virus (HCV) is an important human pathogen that causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. This positive stranded RNA virus is extremely efficient in establishing persistent infection by escaping immune detection or hindering the host immune responses. Recent studies have discovered two important signaling pathways that activate the host innate immunity against viral infection. One of these pathways utilizes members of Toll-like receptor (TLR) family and the other uses the RNA helicase retinoic acid inducible gene I (RIG-I) as the receptors for intracellular viral double stranded RNA (dsRNA), and activation of transcription factors. In this review article, we summarize the interaction of HCV proteins with various host receptors/sensors through one of these two pathways or both, and how they exploit these interactions to escape from host defense mechanisms. For this purpose, we searched data from Pubmed and Google Scholar. We found that three HCV proteins; Core (C), non structural 3/4 A (NS3/4A) and non structural 5A (NS5A) have direct interactions with these two pathways. Core protein only in the monomeric form stimulates TLR2 pathway assisting the virus to evade from the innate immune system. NS3/4A disrupts TLR3 and RIG-1 signaling pathways by cleaving Toll/IL-1 receptor domain-containing adapter inducing IFN-beta (TRIF) and Cardif, the two important adapter proteins of these signaling cascades respectively, thus halting the defense against HCV. NS5A downmodulates the expressions of NKG2D on natural killer cells (NK cells) via TLR4 pathway and impairs the functional ability of these cells. TLRs and RIG-1 pathways have a central role in innate immunity and despite their opposing natures to HCV proteins, when exploited together, HCV as an ever developing virus against host immunity is able to accumulate these mechanisms for near unbeatable survival.
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PMID:Interaction of Hepatitis C virus proteins with pattern recognition receptors. 2272 46


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