Effect of interleukin-10 and platelet-derived growth factor on expressions of matrix metalloproteinases-2 and tissue inhibitor of metalloproteinases-1 in rat fibrotic liver and cultured hepatic stellate cells

Department of Gastroenterology, People's Hospital, Medical School of Wuhan University, Hubei Province, China.
World Journal of Gastroenterology (Impact Factor: 2.37). 09/2004; 10(17). DOI: 10.3748/wjg.v10.i17.2574
Source: DOAJ


AIM: To examine the expressions of matrix metalloprotein-ases-2 (MMP-2) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in rat fibrotic liver and in normal rat hepatic stellate cells, and to investigate the changes in their expressions in response to treatment with interleukin-10 (IL-10) and platelet-derived growth factor (PDGF).
METHODS: Rat models of CCl(4)-induced hepatic fibrosis were established and the liver tissues were sampled from the rats with or without IL-10 treatment, and also from the control rats. The expressions of MMP-2 and TIMP-1 in liver tissues were detected by S-P immunohistochemistry, and their expression intensities were evaluated in different groups. Hepatic stellate cells (HSCs) were isolated from normal rat and cultured in vitro prior to exposure to PDGF treatment or co-treatment with IL-10 and PDGF. MMP-2 and TIMP-1 levels were measured by semi-quantitative reverse transcriptional polymerase chain reaction (RT-PCR).
RESULTS: CCl(4)- induced rat hepatic fibrosis models were successfully established. The positive expressions of MMP-2 and TIMP-1 increased obviously with the development of hepatic fibrosis, especially in untreated model group (84.0% and 92.0%, P<0.01). The positive signals decreased significantly following IL-10 treatment (39.3% and 71.4%, P<0.01 and P<0.05) in a time-dependent manner. TIMP-1 mRNA in PDGF-treated group was significantly increased time-dependently in comparison with that of the control group, but PDGF did not obviously affect MMP-2 expression. No difference was noted in TIMP-1 and MMP-2 expressions in HSCs after IL-10 and PDGF treatment (P>0.05).
CONCLUSION: MMP-2 and TIMP-1 expressions increase in liver tissues with the development of fibrosis, which can be inhibited by exogenous IL-10 inhibitor. PDGF induces the up-regulation of TIMP-1 but not MMP-2 in the HSCs. IL-10 inhibits TIMP-1 and MMP-2 expressions in HSCs induced by PDGF.

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    • "Adiponectin induces expression of several other protective mediators, and an IL-10/HO-1 pathway is involved in the anti-inflammatory effects of adiponectin [33]. IL-10 inhibits intrahepatic fibrogenesis by suppressing production of collagen I [34,35], down-regulating expression of profibrogenic factors TGF-β1, MMP-9 and TNF-α [36-38], and promoting apoptosis of activated HSCs [39]. In addition, IL-10 up-regulates HO-1 expression through the p38 mitogen-activated protein kinase pathway [40,41]. "
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    ABSTRACT: Background Peroxisome proliferator activated receptor alpha (PPARα) ameliorates ethanol induced hepatic steatohepatitis. However, its role in alcoholic liver fibrosis has not been fully clarified. The aim of this study was to elucidate the effect and the molecular basis of PPARα in ethanol induced liver fibrosis in mice. Methods C57BL/6J mice were fed with 4% ethanol-containing Lieber-DeCarli liquid diet for eight weeks, and intraperitoneal injected with 5% carbon tetrachloride (CCl4) for the last four weeks to induce alcoholic liver fibrosis. PPARα agonist WY14643 was administered to mice during the last couple of weeks. The effects of PPARα induction on liver histology, activation of hepatic stellate cells (HSCs), as well as hepatic expression of inflammatory and fibrogenic factors were assessed. Results The ethanol plus CCl4 treated mice exhibited progressive liver injury including piecemeal necrosis of hepatocytes, severe inflammatory cells infiltration and bridging fibrosis. This was accompanied by down-regulated hepatic expression of PPARα and the protective cytokines adiponectin, heme oxygenase-1 and interleukin-10. Additionally, up-regulation of the proinflammatory cytokine tumor necrosis factor-alpha, as well as the profibrogenic genes osteopontin, transforming growth factor-beta 1, visfatin, phosphatidylinositol 3-kinase, matrix metalloproteinase-2 (MMP-2) and MMP-9 was observed. WY14643 treatment restored expression of cytokines altered by ethanol plus CCl4 treatment and concomitantly ameliorated the liver injury. Conclusions The present study provides evidence for the protective role of PPARα induction in ameliorating ethanol mediated fibrosis through mediation of inflammatory and fibrogenic factors.
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    ABSTRACT: Current evidence indicates that liver fibrosis is a dynamic and bidirectional process. In chronic liver diseases, Hepatic stellate cells (HSCs) undergo a process of activation towards a myofibroblast-like phenotype, migrate, accumulate at the sites of tissue repair and acquires an increased expression of alpha-smooth muscle actin (α-SMA). The aim of this study is to assess fibrosis by evaluation of the expression of α-smooth muscle actin as marker of activated HSCs in chronic hepatitis C patients. Liver biopsies were obtained from 26 patients with hepatitis C virus infection confirmed by PCR. Histopathological diagnosis and determination of the grade and stage of fibrosis was done according to Modified Hepatitis Activity Index (HAI). Immunohistochemical staining was done with primary monoclonal mouse α-SMA (SM-alpha actin, Dako A/S, Denmark). Our results showed an increased immunostaining positivity with the increase of the HAI grading (directly proportional) but with no statistical significance (p value = 0.323). Regarding correlation between stage of fibrosis and α-SMA, there is a highly significant correlation as all the 6 cases of stage 0/6 were negative and 4/7 case of stage 1/6 were positive; this percentage increase with the increases of the stage of fibrosis to reach 100% from the stage 4/6 to the stage 6/6 which is statistically significant (p value = 0.027). Also the degree of positivity increase with the stage of fibrosis with highly significant variation (p value = 0.008). α-SMA correlates with the stage of fibrosis. There is a direct correlation between activated HSCs and the progression of fibrosis. Although there is no standard treatment for liver fibrosis, but antifibrotic drugs which can target these cells in order to stop their activation can be an important clue in future therapeutic strategies.
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    ABSTRACT: Silybin is a flavonoid extracted from the herb Armurariu (Silybum marianum) and has the potential efficacy in the treatment of liver disease. The aims of this study were to investigate the effect of alcohol and CCl4 on liver histology and the capacity of silybin to ameliorate the hepatotoxicity. Thirty adult male Wistar rats were used in the study. Liver toxicity was induced by dietary alcohol administration and CCl4 intra-peritoneal injection. The protective effect of silibin was investigated by co-administration of silybin with these toxic agents. Hepatocellular and extracellular matrix integrity was determined by histopathological and immunohistochemical study. Hematoxylin-Eosin and trichrome stains sections were studied in each case. For immunohistochemistry we used monoclonal anti-collagen IV primary antibody. Light microscopic evaluation of liver tissues shows that control and silibin treated groups has normal liver structure. In the toxicity groups, HE and trichromic staining showed hepatocellular necrosis, inflammatory infiltrate and proliferating collagen fibers. Immunoexpression of collagen IV was variable. In the control group, we found negative expression. Collagen IV displays positive immunoreaction in hepatotoxicity groups, at the level of the areas rich in inflammatory infiltrate and with degenerative aspect. After this study, we can conclude that silybin, in rats, has protective effects.
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