Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the hypothesis that Th1 phenotype cytokines are associated with the increasing activity of hepatitis and Th2 phenotype cytokines with decreasing activity in the liver of chronic viral hepatitis, expressions of the mRNA of the cytokines IL-2, IFN-gamma and IL-4 in the liver of 23 patients with chronic hepatitis B were investigated by reverse transcription polymerase chain reaction. Patients were divided into three groups according to the phase of acute exacerbation of hepatitis as increasing (n = 9), decreasing (n = 8), and stable phase (n = 6). Both IL-2 and IFN-gamma mRNA were preferentially expressed in increasing phase than in decreasing phase (P < 0.01, P < 0.05, respectively) and associated with the high serum alanine aminotransferase (ALT) level. On the other hand, IL-4 mRNA was detected in decreasing phase with significant frequency compared with increasing phase (P < 0.05). However, expression of IL-4 mRNA was not associated with serum ALT level. Our results suggest that Th1 phenotype cytokines up-regulate and Th2 phenotype cytokines down-regulate the liver inflammation of chronic viral hepatitis.
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PMID:The expression of IL-2, IL-4 and interferon-gamma (IFN-gamma) mRNA using liver biopsies at different phases of acute exacerbation of chronic hepatitis B. 777 54

T lymphocytes and immunoregulatory cytokines may be important in the host response to hepatitis C virus (HCV) infection. T-helper type 1 (Th1) cytokines (interleukin [IL]-2, interferon gamma [IFN-gamma]) are required for host antiviral immune responses, including cytotoxic T-cell generation and natural killer cell activation, while T-helper type 2 (Th2) cytokines (IL-4,IL-10) can inhibit the development of these effector mechanisms. In this study, the serum levels of Th1 and Th2 cytokines in patients (n = 23) infected with HCV were measured and compared with biochemical (alanine transaminase [ALT]) and viral (HCV RNA) indicators of infection. Serial cytokine levels were measured in a subset of 11 patients at 1 and 12 weeks during and at 1 week after interferon alfa (IFN-alpha) therapy (n = 33 samples). Levels of circulating IL-2, IL-4, IL-10, and IFN-gamma were significantly elevated in HCV patients versus normal controls (128 vs. 25 pg/mL, 3,045 vs. 29 pg/mL, 2,949 vs. 18 pg/mL, and 307 vs. 24 pg/mL respectively; P < .01). Treatment with IFN-alpha decreased the levels of IL-4 (321 +/- 224 pg/mL), and IL-10 (1,011 +/- 344 pg/mL), which paralleled a decrease in HCV RNA (114 +/- 27 vs. 25 +/- 20 Eq/ml X 10(5), pre- vs. post-IFN-alpha [12 weeks];P <.05). These findings indicate that an activated T-cell response, as manifest by increased circulating immunoregulatory cytokines, is present in patients with HCV liver disease. Furthermore, treatment with HCV liver disease. Furthermore, treatment with IFN-alpha diminishes the Th2 cytokine response. Thus, modulation of T-cell function and cytokine production may be one mechanism whereby IFN-alpha therapy results in reduced viral burden.
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PMID:Immunoregulatory cytokines in chronic hepatitis C virus infection: pre- and posttreatment with interferon alfa. 870 83

Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in mediating hepatic fibrogenesis and is known to have negative regulatory effects on the immune system. To analyse the effects of TGF-beta 1 in chronic HCV, serum samples were prospectively collected from 88 chronic hepatitis C virus (HCV) patients and 34 healthy controls. Total and biologically active TGF-beta 1, interleukin (IL)-4 and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA). HCV RNA levels were quantified by branched DNA signal amplification pathway (bDNA), and HCV genotypes were determined by restriction fragment length polymorphism (RFLP) based on the 5'-untranslated region (UTR). Histological diagnosis was available in 87 patients, and liver sections from 80 other HCV patients were evaluated for hepatic expression of TGF-beta 1 using immunohistochemistry. Patients with chronic HCV infection had a higher level of TGF-beta 1, both total (817 +/- 464 ng ml-1) and biologically active forms (520 +/- 370 pg ml-1), compared with controls (total TGF-beta 1 183 +/- 105 ng ml-1, P < 0.001; active TGF-beta 1 290 +/- 140 pg ml-1, P < 0.01). There was no correlation between either total or biologically active TGF-beta 1 and clinical variables (age, gender, duration), liver biochemistry (serum alanine aminotransferase) or virological (HCV RNA level, genotype) parameters but there was a correlation between total TGF-beta 1 and Knodell scores (P = 0.03, n = 54). However, when individual histological parameters were analysed, only the fibrosis score showed significant correlation (P = 0.04, n = 54). Immunohistochemistry revealed that 62% of HCV patients had TGF-beta 1 present in sinusoidal cells. No correlation existed between hepatic expression of TGF-beta 1 and any histological parameters. A trend existed towards a correlation between total TGF-beta 1 and IL-4 (P = 0.059, n = 74) but not with IL-10. Therefore, the TGF-beta 1 system is activated in chronic HCV infection and may contribute towards hepatic fibrogenesis; in addition, the TGF-beta 1 system may interact with IL-4.
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PMID:Transforming growth factor-beta 1 in chronic hepatitis C. 903 Oct 62

We studied whether the infection with a blood-stage murine malaria lethal Plasmodium berghei NK65 induces IL-12 production, and if so, how the IL-12 production is involved in the protection or pathogenesis. The infection of C57BL/6 mice enhanced mRNA expression of IL-12 p40 and also IFN-gamma, IL-4, and IL-10 in both spleen and liver during the early course of the infection. It also enhanced the mRNA expression of TNF-alpha, Fas ligand, and cytokine-inducible nitric oxide synthase. Increased IL-12 p40 production was also observed in the culture supernatant of spleen cells and in sera of infected mice. In addition, the infection caused massive liver injury with elevated serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and body weight loss. Treatment of these infected mice with neutralizing mAb against IL-12 prolonged the survival and diminished the liver injury with reduced elevation of serum serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and decreased body weight loss. However, the anti-IL-12 treatment did not affect parasitemia, and all these mice eventually died. Similar results were obtained when infected mice were treated with neutralizing mAb against IFN-gamma. Moreover, anti-IL-12 treatment greatly reduced the secretion and mRNA expression of IFN-gamma in both spleen and liver. These results suggest that the lethal P. berghei NK65 infection induces IL-12 production and that the IL-12 is involved in the pathogenesis of liver injury via IFN-gamma production rather than the protection.
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PMID:A pathogenic role of IL-12 in blood-stage murine malaria lethal strain Plasmodium berghei NK65 infection. 960 53

Ribavirin is effective in combination therapies against chronic hepatitis C virus (HCV) infection, although its direct antiviral properties are unclear. We therefore studied the immune-modulatory effects of ribavirin on hepatitis B virus (HBV)- and HCV-specific immune responses. During a 24 week placebo-controlled ribavirin trial in ten patients with chronic HCV infection, HCV antibodies and alanine aminotransferase (ALT) levels decreased transiently whereas the serum levels of HCV RNA remained stable. Effects of ribavirin on human and murine phytohaemagglutinin (PHA)-activated T cells included inhibition of in vitro proliferation and modulation of IL-2, IL-4, IFN-gamma and TNF-alpha levels. HBcAg- and HBeAg-specific IL-2 and IFN-gamma levels were > or = 25-fold higher in mice immunized with HBV core- or e-antigens (HBcAg, HBeAg) while receiving ribavirin compared to untreated mice, but IL-4 and IL-6 remained constant. Concordantly, a slight shift was observed in the IgG subclass distribution of the humoral responses of ribavirin-treated mice to HBeAg and HCV NS3 protein. Ribavirin treatment of HBeAg-transgenic (HBeAg-Tg) mice induced a dose-dependent down-regulation of T helper (Th)2-mediated antibody production to HBeAg. In ribavirin-treated HBeAg-Tg mice anti-HBe IgG1 (positively regulated by Th2 cytokines) decreased simultaneously as both anti-HBe IgG2a (positively regulated by Th1 cytokines) levels and in vitro T-cell IFN-gamma production increased, indicating a change in the Th1/Th2 balance. Thus, the present data suggest that ribavirin is not strictly an antiviral compound, but rather it alters the T-cell balance in the immune system.
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PMID:The antiviral compound ribavirin modulates the T helper (Th) 1/Th2 subset balance in hepatitis B and C virus-specific immune responses. 978 43

The proto-oncogene product bcl-2 is known to inhibit apoptotic cell death, and its dysregulation might play a critical role in the development of autoimmune disease. To elucidate the role of bcl-2 in autoimmune hepatitis (AIH), its expression in peripheral blood mononuclear cells (PBMC) and in liver-infiltrating lymphocytes (LIL) was investigated. Increased bcl-2 expression in PBMC was found in AIH patients compared with that in chronic hepatitis C (CHC) patients and in healthy controls. The level of bcl-2 expression significantly correlated with serum ALT level. Further analysis showed that CD4+ T cells are enriched in bcl-2-expressing PBMC. To characterize the Th1/Th2 profile of bcl-2-expressing CD4+ T cells, intracellular interferon-gamma (IFN-gamma) and IL-4 were analysed. The results revealed that most of the bcl-2-expressing cells were found to be IFN-gamma-secreting Th1 cells. In three patients for whom their clinical courses could be followed, bcl-2 expression was decreased after the initiation of immunosuppressive therapy with corticosteroids. However, the level of IFN-gamma + cells was not altered. Immunohistochemical analysis also showed that large amounts of bcl-2+ cells were observed in periportal area in the liver. In conclusion, bcl-2-expressing cells were shown to be increased in peripheral blood and liver in AIH and the bcl-2 product was expressed mainly in CD4+ Th1-type cells, suggesting that these cells might promote the cellular immune response and contribute to the development of hepatitis and hepatocellular damage in AIH.
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PMID:Increased bcl-2 expression in lymphocytes and its association with hepatocellular damage in patients with autoimmune hepatitis. 1020 18

The cytokine pattern on viral antigen recognition is believed to exert a profound influence on the resolution of viral infections and viral clearance. This study was initiated to investigate whether a cytokine imbalance oriented toward Th2 type response plays a role in chronic hepatitis B. Cytokine profiles of peripheral blood mononuclear cells associated with chronic hepatitis B were analysed by RT-PCR. Upon HBsAg stimulation, expression of IFN-gamma, IL-2, IL-4, and IL-10 was detected in 41%, 8%, 41%, and 50% of the patients, respectively. Among these cytokines, the expression of IFN-gamma was associated with high levels of serum AST/ALT. However, we could not prove that Th2 type cytokines had a protective effect on hepatocytes. Upon HBxAg stimulation, there was no recognizable association of cytokine patterns with AST/ALT levels. In conclusion, production of a Th1 cytokine, IFN-gamma, by HBsAg-reactive cells was associated with hepatocyte damage in chronic hepatitis B, while no counteracting effect of Th2 cytokines produced by those cells was observed.
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PMID:Expression of Th1 and Th2 type cytokines responding to HBsAg and HBxAg in chronic hepatitis B patients. 1033 64

As variable functions of cytokines have been proved in recent years, cytokine levels in biological fluids such as serum, plasma, and synovial fluid of patients with every kind of disease have been enthusiastically measured. As a result, many studies have shown an increase or decrease in the production of cytokines or abnormal cytokine levels in biological fluids. However, the relationship between the abnormal levels of cytokines and the intensity of the clinical symptoms or the prognosis remains unclear. The significance for the measurement of cytokines depends on whether it should be valid for detecting a preclinical status such as AST or ALT used for health checks or for disease screening such as some tumor markers. The purpose of this study is to know whether or not some cytokine levels in serum could be biomarkers for preventive purposes. Serum cytokine levels (IL-4, 6, 8, 12, and IFN-gamma) were measured in three different types of cohorts (nursery school infants, manufacturing workers and middle and old aged women) with chemiluminescence ELISA. The results showed no differences with atopic status in infants, pulmonary fibrosis in workers or with the decrease in bone stiffness, these results are mainly due to a great inter-individual variability of serum cytokine levels. This study concludes that serum cytokine levels are inappropriate as biomarkers for preventive purposes. However, a further detailed evaluation in healthy people with high serum cytokine levels may be necessary.
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PMID:[The public health significance of the measurement of cytokines in serum]. 1071 50

The present study demonstrates that the quality of the virus-specific CD8(+) T cell responses, as detected by both enzyme-linked immunospot assay and specific MHC-peptide tetramers, changed in relation to the different disease activity in chronically hepatitis C virus-infected patients. Indeed, both the serum alanine transaminase and the hepatic flogosis levels were related directly to the frequencies of peripheral memory effector CD8(+) T cells producing IFN-gamma (Tc1), but inversely to the frequencies of those producing both IL-4 and IL-10 (Tc2). Longitudinal studies highlighted that Tc1 or Tc2 responses fluctuate in relation to the different phases of the disease in the same individual. Furthermore, the Tc1 or Tc2 phenotype correlates with tetramer-positive cells expressing either CXCR3 or CCR3, promoting differential tissue localization of these cells and the maintenance of T cell homeostasis. Finally, studies at the level of liver-infiltrating lymphocytes indicated that they produced both IFN-gamma and IL-4 with an evident bias towards the Tc1-like phenotype. Our studies suggest that the progressive fluctuation of Tc1 and Tc2 responses may play a fundamental role in maintaining a long-lasting low-level liver inflammation, and may constitute the basis for new therapeutic strategies of immune regulation.
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PMID:Virus-specific CD8(+) T cells with type 1 or type 2 cytokine profile are related to different disease activity in chronic hepatitis C virus infection. 1124 Dec 95

Recent studies in vitro and in animals have suggested that ribavirin may potentiate the antihepatitis C virus (HCV) activity of interferon-alpha (IFN-alpha) by up-modulating the production of T cell-derived cytokines, such as interleukin (IL)-2 and IFN-gamma, which play a key role in the cellular immune response against HCV. To study the immune-modulatory mechanisms of ribavirin further, cytokine production by activated T cells and circulating cytokine levels were studied by FACS analysis and ELISA testing in 25 patients with chronic hepatitis C unresponsive to IFN-alpha, before and after treatment with either ribavirin plus IFN-alpha or IFN-alpha alone. After 16 weeks of treatment, both the expression of IFN-gamma by activated T cells and the blood levels of IFN-gamma, were significantly reduced with respect to pretreatment values in patients treated with ribavirin and IFN-alpha but not in those undergoing treatment with IFN-alpha alone. The expression of IFN-gamma was significantly lower in patients that gained normal ALT levels with respect to those that did not. No modification of the expression of IL-2, IL-4 and IL-10 was found before and after treatment in either group of patients. In conclusion, the results of this study do not support up-modulation of IFN-gamma and IL-2 production as the mechanism by which ribavirin potentiates IFN-alpha anti HCV activity. In addition, our findings suggest that ribavirin may exert an anti-inflammatory effect and may help reducing IFN-gamma-driven T cell activation and liver damage.
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PMID:Treatment with ribavirin and interferon-alpha reduces interferon-gamma expression in patients with chronic hepatitis C. 1129 34


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