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      Role of transforming growth factor-β1 in serum and − 509 C>T promoter gene polymorphism in development of liver cirrhosis in Egyptian patients

      research-article
      a , * , b
      Meta Gene
      Elsevier
      Transforming growth factor-β1 (TGF-β1), Liver cirrhosis, PCR-RFLP

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          Abstract

          Objectives

          Liver cirrhosis is a condition in which the liver slowly deteriorates and malfunctions due to chronic injury. HCV is one of the major causes of liver fibrosis and ultimate progression to cirrhosis. Transforming growth factor-beta1 (TGF-β1), one of the three isoforms of TGF-β, is a pleiotrophic cytokine that regulates the proliferation and differentiation of cells, embryonic development, wound healing and angiogenesis. This study aimed to evaluate the role of serum TGF-β1 and − 509 C>T promoter gene polymorphism in the development of liver cirrhosis.

          Design and methods

          Besides routine liver profiles, serum TGF-β1 was measured in 40 liver cirrhosis patients and 40 controls using ELISA technique. TGF-β1 − 509 C>T promoter gene polymorphism was detected using PCR-RFLP technique.

          Results

          TGF-β1 − 509 CT and TT genotype frequencies were significantly higher in the cirrhotic group (52.5%, 25%; respectively) than control group (10%, 7.5%; respectively); OR = 16.238 (95% CI 5.391–48.914, p < 0.05). The − 509 T allele carriers are more prone to develop liver cirrhosis than − 509 C allele carriers; OR = 7.359 (95% CI 3.325–16.288, p < 0.05). Serum TGF-β1 was significantly higher in cirrhotic group (11.79 ± 1.45 ng/ml) than control group (8.67 ± 1.23 ng/ml); p < 0.05. Also serum TGF-β1 was significantly higher in TT genotype than CT and CC genotypes ( p < 0.05). A significant positive correlation was observed between serum TGF-β1 and alkaline phosphatase (r = 0.559, p < 0.05); AST (r = 0.573, p < 0.05). A significant negative correlation was observed between serum TGF-β1 and albumin (r = − 0.331, p < 0.05).

          Conclusion

          There is an association between serum TGF-β1, − 509 CT and TT genotypes of TGF-β1 gene and the higher risk for liver cirrhosis development of liver cirrhosis.

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          Most cited references20

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          Liver fibrosis.

          Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.
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            Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma.

            Many patients with chronic hepatitis caused by hepatitis C virus (HCV) infection develop liver fibrosis with high risk for hepatocellular carcinoma (HCC), but the mechanism underling this process is unclear. Conversely, transforming growth factor beta (TGF-beta) activates not only TGF-beta type I receptor (TbetaRI) but also c-Jun N-terminal kinase (JNK), which convert the mediator Smad3 into two distinctive phosphoisoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). Whereas the TbetaRI/pSmad3C pathway suppresses epithelial cell growth by upregulating p21(WAF1) transcription, JNK/pSmad3L-mediated signaling promotes extracellular matrix deposition, partly, by upregulating plasminogen activator inhibitor 1 (PAI-1). We studied the domain-specific Smad3 phosphorylation in biopsy specimens representing chronic hepatitis, cirrhosis, or HCC from 100 patients chronically infected with HCV, and correlated Smad3 phosphorylation with clinical course. As HCV-infected livers progressed from chronic hepatitis through cirrhosis to HCC, hepatocytic pSmad3L/PAI-1 increased with fibrotic stage and necroinflammatory grade, and pSmad3C/p21(WAF1) decreased. Of 14 patients with chronic hepatitis C with strong hepatocytic pSmad3L positivity, 8 developed HCC within 12 years; only 1 of 12 showing little pSmad3L positivity developed HCC. We further sought molecular mechanisms in vitro. JNK activation by the pro-inflammatory cytokine interleukin-1beta stimulated the pSmad3L/PAI-1 pathway in facilitating hepatocytic invasion, in the meantime reducing TGF-beta-dependent tumor-suppressive activity by the pSmad3C/p21(WAF1) pathway. These results indicate that chronic inflammation associated with HCV infection shifts hepatocytic TGF-beta signaling from tumor-suppression to fibrogenesis, accelerating liver fibrosis and increasing risk for HCC.
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              Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease.

              Several lines of evidence suggest that local production of transforming growth factor-beta (TGF-beta) contributes to renal disease, particularly to the accumulation of the extracellular matrix protein that characterizes glomerulosclerosis and interstitial fibrosis. We have examined whether elevated levels of circulating TGF-beta adversely affect the kidney. We have studied mice that are transgenic for an active form of TGF-beta 1 under the control of murine albumin promoter and enhancer DNA sequences. These mice express the transgene exclusively in the liver and have elevated plasma concentrations of TGF-beta 1. Renal disease was seen in two of three lines of Alb/TGF-beta 1 transgenic mice; these two lines had the highest levels of hepatic transgene expression and the highest plasma TGF-beta 1 levels. Histologic abnormalities, which included mesangial expansion and thickened capillary loops, were noted in the glomeruli by 3 weeks of age. Interstitial fibrosis and tubular atrophy appeared subsequently. Mice from Line 25, the line with highest levels of TGF-beta 1, developed proteinuria by 5 weeks of age. These mice subsequently manifested nephrotic syndrome with ascites and progressive azotemia; uremic death occurred in more than 25% of the mice by 15 weeks of age. The glomeruli contained immune deposits in subendothelial and mesangial locations, but complement deposition was infrequent. Ultrastructural examination revealed an increase in extracellular matrix material, including collagen fibrils, in subendothelial and mesangial locations. Increased levels of circulating TGF-beta 1 induced progressive renal disease that was characterized by mesangial expansion, accumulation of glomerular immune deposits and matrix proteins, and interstitial fibrosis in this transgenic mouse model. These data suggest that chronically elevated circulating levels of TGF-beta 1 induce progressive glomerulosclerosis.
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                Author and article information

                Contributors
                Journal
                Meta Gene
                Meta Gene
                Meta Gene
                Elsevier
                2214-5400
                09 September 2014
                December 2014
                09 September 2014
                : 2
                : 631-637
                Affiliations
                [a ]Clinical and Chemical Pathology Department, Cairo University, Egypt
                [b ]Tropical Medicine Department, Cairo University, Egypt
                Author notes
                [* ]Corresponding author. Tel.: + 20 1005162951. abeermohy@ 123456hotmail.com
                Article
                S2214-5400(14)00051-6
                10.1016/j.mgene.2014.08.002
                4287823
                25606446
                88a0a679-d12b-4d94-bda9-a798092f8447
                © 2014 Published by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                : 23 June 2014
                : 10 August 2014
                : 11 August 2014
                Categories
                Article

                transforming growth factor-β1 (tgf-β1),liver cirrhosis,pcr-rflp

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