Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The novel human gene MIA2 encoding a melanoma inhibitory activity (MIA) homologous protein was identified by a GenBank(TM) search. MIA2, together with MIA, OTOR, and TANGO, belongs to the novel MIA gene family sharing important structural features, significant homology at both the nucleotide and protein levels, and similar genomic organization. In situ hybridization, reverse transcriptase-PCR, and Northern blots presented a highly tissue-specific MIA2 expression pattern in the liver. Promoter studies analyzing transcriptional regulation of MIA2 revealed an HNF-1-binding site at position -236 controlling hepatocyte-specific expression. Mutation of the site led to a complete loss of promoter activity in HepG2 cell. Further sites detected in the MIA2 promoter were consensus binding sites for SMAD and STAT3, Consistently, stimulation of MIA2 mRNA expression occurred by treatment with interleukin-6, transforming growth factor-beta, and conditioned medium from activated hepatic stellate cells. In accordance with these results, MIA2 mRNA was found to be increased in liver tissue of patients with chronic hepatitis C infection compared with controls. MIA2 mRNA levels were significantly higher in patients with severe fibrosis or inflammation than in patients with less severe fibrosis or inflammation. In summary our data indicate that MIA2 represents a potential novel acute phase protein and MIA2 expression responds to liver damage. The increased transcription in more severe chronic liver disease suggests that MIA2 may serve as a marker of hepatic disease activity and severity.
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PMID:Specific expression and regulation of the new melanoma inhibitory activity-related gene MIA2 in hepatocytes. 1258 26

Liver cirrhosis is characterized by a severe impairment of the growth hormone/insulin-like growth factor-1 (GH-IGF-1) axis, that is, acquired GH resistance. The condition of the GH-IGF-1 axis in the phase of chronic liver disease (CLD) preceding cirrhosis, however, remains uncertain. The origin of GH resistance during CLD is multifactorial, and to date, the liver functional mass is considered to play a major role. Although proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, were found to be elevated in patients with CLD and were shown to induce a state of GH resistance in other disease models, their involvement in the pathogenesis of GH resistance during CLD has never been investigated. We characterized the GH-IGF-1 axis by analyzing the individual components of the axis (GH, IGF-1, IGF-binding protein-3 [IGFBP-3], acid-labile subunit [ALS]) and the corresponding ratios (GH/IGF-1, GH/IGFBP-3, and GH/ALS) and verified the links with circulating proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), in 34 patients with CLD and 12 healthy controls. Evolution of CLD from chronic hepatitis (CH, n = 17) to cirrhosis (CIR, n = 17) was associated with a progressive increase of GH resistance indices (e.g., GH/IGF-1 ratio: controls 0.5 +/- 0.9, CH 15.9 +/- 31.2, p < 0.01 vs. controls; CIR 188.4 +/- 282.7 mU/nmol, p < 0.001 vs. CH and controls), indicating its onset also in the early stages of CLD. The progressive increase in GH resistance indices matched the increase of circulatory TNF-alpha (e.g., TNF-alpha vs. GH/IGF-1, r = 0.54, p < 0.001). A similar trend was found for IL-6 without reaching statistical significance (r = 0.23, p = 0.13). We found undetectable levels of IL-1beta in our sample of patients and controls. We conclude that proinflammatory cytokines play an important role in the pathogenesis of GH resistance in CLD, but TNF-alpha is a major factor. In addition, GH resistance is present in CLD from the early stages. These results could begin new therapeutic lines of attack in the management of CLD.
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PMID:TNF-alpha and growth hormone resistance in patients with chronic liver disease. 1280 65

Partial hepatectomy is a major upper abdominal operation associated with certain stress to the patient. Successful adaptation to such stress is a prerequisite for survival. Donor hepatectomy with maximal safety is a principal concern during living donor liver transplantation. The purpose of the study was to compare the stress response by assessing cytokines and the acute-phase response induced by hepatectomy in patients with a healthy liver and those with a diseased liver. Fourteen patients undergoing partial right hepatectomy were enrolled in this study. Seven of them were donors for living related liver transplantation (group 1, or GI); the other seven were patients with hepatocellular carcinoma due to chronic hepatitis B (Child's class A) (GII). Blood samples for interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), and C-reactive protein (CRP) assays were collected before the operation, at the beginning and end of the operation, and 24 and 48 hours after the operation. The data were analyzed and compared in the same group using the Friedman test and between groups using the Mann-Whitney U-test. A value of p < 0.05 was regarded as significant. Results showed that resection of the liver in patients with both healthy and disease livers leads to significant increases in IL-6 and CPR but not TNFalpha. Significantly lower levels of IL-6 before and after operation in GI patients compared to those in GII patients suggests that GI patients adapted to surgical stress more easily than did the GII patients.
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PMID:Stress response to hepatectomy in patients with a healthy or a diseased liver. 1450 1

The chronic hepatitis B virus (HBV) carrier exhibits ongoing replication of HBV and expresses abundant amounts of HBV-related antigens in the liver. However, HBV-specific immune responses are either absent or narrowly focused in these subjects. With the postulation that impaired functional abilities of liver dendritic cells (DCs) might be responsible for this, we assessed the functions of liver DCs in HBV transgenic mice (HBV-TM), an animal model of the HBV carrier state. Liver DCs were isolated from normal C57BL/6 mice and HBV-TM without the use of cytokines or growth factors. Lymphoproliferative assays were conducted to evaluate the ability of liver DCs to induce the proliferation of allogenic T lymphocytes and hepatitis B surface antigen (HBsAg)-enriched T lymphocytes. Liver DCs were stimulated with viral and bacterial products to assess their cytokine-producing capacities. In comparison to liver DCs from normal C57BL/6 mice, liver DCs from HBV-TM exhibited significantly decreased T cell proliferation-inducing capacities in allogenic mixed leucocyte reaction (P <0.05) and HBsAg-enriched T lymphocytes proliferation assays (P <0.05). Liver DCs from HBV-TM produced significantly lower levels of interleukin-12p70, tumour necrosis factor-alpha, interferon-gamma, and interleukin-6 (P <0.05) compared to liver DCs from normal C57BL/6 mice. This study provides evidence that liver DCs from HBV-TM had impaired ability to induce both innate and adaptive immune responses. This might account for a weak and almost undetectable HBV-specific immune response in chronic HBV carriers. This inspires hope that up-regulation of the functions of liver DCs in situ may have therapeutic implications in chronic HBV carriers.
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PMID:Impaired functional capacities of liver dendritic cells from murine hepatitis B virus (HBV) carriers: relevance to low HBV-specific immune responses. 1560 11

The aim of this study was to evaluate a possible relationship between lymphomonocyte expression of heat shock proteins (HSP) 60/27 and plasma levels of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) and markers of antioxidant/oxidative status [glutathione (GSH), alpha glutathione-S-transferase activity (alpha GST), malonyldialdeyde (MDA), 4-hydroxinonenal (4-HNE), and S-nitrosothiols (S-NO)] in patients with chronic liver diseases. Entered into the study were 47 subjects: 10 healthy controls, 16 patients with HCV-related chronic hepatitis (CH), and 16 patients with HCV-related and 5 with alcohol-related liver cirrhosis (10 Child A and 11 Child B+C). HSP60 was clearly expressed only in 5% of patients and lowly in the control group. HSP27 was clearly expressed in 46.7% of CH and 71.4% of cirrhotic patients but was lowly present in healthy subjects. A significant difference was found between patients with a low expression of HSP27 (negative patients) and those with a high HSP27 expression (positive patients) of plasma levels both of antioxidants (GSH, p < 0.05), and of markers of enhanced production of free radicals and cytokines (alpha GST, TNF-alpha and IL-6, p < 0.05; MDA, 4-HNE and S-NO, p < 0.01) as well as for alcohol use and degree of liver impairment. The present data are the first showing that, particularly in conditions of enhanced oxidative stress, lymphomonocytes from liver disease patients present an increased expression of HSP27.
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PMID:Heat shock protein 27 expression in patients with chronic liver damage. 1596 49

Interleukin-6 (IL-6) is an important cytokine in liver regeneration, and elevated levels of IL-6 have been demonstrated in patients with chronic liver diseases (CLD). Many biological effects of IL-6 depend on naturally occurring soluble IL-6 receptors. In the present study we measured the concentrations of IL-6 and its soluble receptors in the sera of patients with CLD related to hepatitis C virus (HCV) infection. We studied 77 patients with varying degrees of HCV-related CLD. Serum levels of IL-6 and its soluble receptors (sIL-6R, sgp130) were measured by enzyme-linked immunosorbent assay. Serum IL-6 and sIL-6R were elevated in patients with CLD compared with healthy subjects. Serum levels of sgp130 did not differ between patients with chronic hepatitis and healthy subjects. However, in patients with liver cirrhosis, sgp130 was significantly elevated and was positively correlated with total bilirubin and negatively correlated with cholinesterase and prothrombin time. Our study demonstrated that in patients with HCV-related CLD, serum IL-6 and its soluble receptor levels are correlated with both liver function impairment and the degree of liver fibrosis. These observations suggest that the balance of IL-6 and its soluble receptors may correspond to the state of liver damage in patients with CLD.
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PMID:Serum levels of interleukin-6 and its soluble receptors in patients with hepatitis C virus infection. 1669 22

Depression and fatigue are frequent side effects of interferon-alpha (IFN-alpha) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The 'low IL-6' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size = 0.7 at week 24; F = 9.4, d.f. = 436, P = 0.002). The 'high transcription' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size = 0.2 at week 24; F = 4.5, d.f. = 436, P = 0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F = 1.2, d.f. = 430, P = 0.2; 5-HTT: F = 0.5, d.f. = 430, P = 0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F = 5.0, d.f. = 434, P = 0.02): the 'protective' effect of the 5-HTTLPR polymorphism was evident only in the presence of the 'low IL-6' genotype (F = 5.4, d.f. = 64, P = 0.02), not in the presence of the 'high IL-6' genotype (F = 2.2, d.f. = 369, P = 0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.
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PMID:Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment. 1845 77

Increased interleukin-6 (IL-6) production is implicated in the pathogenesis of hepatocellular carcinoma (HCC) in animal models. Although previous studies showed that HCC patients had higher serum IL-6 level at the time of diagnosis, it is unclear if the cytokine contributes to the development of HCC or is just a reaction to cancer. To address this question, we performed a nested case-control study. Consecutive chronic hepatitis B patients were recruited from 1997 to 2000 and followed till 2008. Profiling of 27 cytokines, chemokines and growth factors was performed at baseline, date of peak alanine aminotransferase (ALT) level and the last visit. Thirty-seven patients developed HCC at a median follow-up of 62 months (interquartile range: 41-110). Serum IL-6 was higher in patients with HCC than controls both during peak ALT and at the last visit (both p = 0.02). Patients with IL-6 above 7 pg/ml during peak ALT had increased risk of HCC or death (adjusted hazard ratio 3.0; 95% confidence interval 1.2, 7.8; p = 0.02). The sensitivity, specificity, positive and negative predictive values of this cutoff to predict future HCC development were 70%, 73%, 72% and 71%, respectively. Combination of IL-6 and AFP improved the sensitivity in diagnosing HCC or predicting future HCC development. In conclusion, high serum IL-6 level predates the development of HCC in chronic hepatitis B patients, and has moderate accuracy in predicting future cancer. This may assist clinicians in selecting high-risk patients for HCC surveillance program.
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PMID:High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. 1926 6

Oncostatin M (OSM), a member of the interleukin-6 family, possesses various functions, including hepatocyte differentiation and suppression of melanoma cell growth. Here, we report anti-hepatitis C virus (HCV) activity of OSM as a new function of this cytokine. OSM possessed marked anti-HCV activity (50% effective concentration: 0.71 ng/ml) in an HCV RNA replication cell culture system. The most striking finding is that OSM exhibited synergistic inhibitory activity on interferon (IFN)-alpha even at a low concentration with weak anti-HCV activity, such as 25 pg/ml. OSM is a candidate anti-HCV reagent and may improve the current IFN therapy for patients with chronic hepatitis C.
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PMID:Oncostatin M synergistically inhibits HCV RNA replication in combination with interferon-alpha. 1933 62

Interleukin-6 (IL-6) is a pleiotropic cytokine with pivotal functions in the regulation of the biological responses of several target cells including hepatocytes. The level of serum IL-6 has been reported to be elevated in patients with chronic hepatitis B, cirrhosis and hepatocellular carcinoma and represents the best marker of HBV-related clinical progression as compared with several other cytokines. In this study, we found that IL-6 was able to effectively suppress hepatitis B virus (HBV) replication and prevent the accumulation of HBV covalently closed circular DNA (cccDNA) in a human hepatoma cell line. We also demonstrated that the suppression of HBV replication by IL-6 requires concurrently a moderate reduction of viral transcripts/core proteins and a marked decrease in viral genome-containing nucleocapsids. Studies on the stability of existing viral capsids suggest that the IL-6 effect on the reduction of genome-containing nucleocapsids is mediated through the prevention of the formation of genome-containing nucleocapsids, which is similar to the effect of interferons. However, IFN-alpha/beta and IFN-gamma did not participate in the IL-6-induced suppression of HBV replication. Taken together, our results will provide important information to better understand the role of IL-6 in the course of HBV infection.
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PMID:HBV replication is significantly reduced by IL-6. 1937 79


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