HepG2 HUMAN HEPATOMA CELLS EXPRESS MULTIPLE CYTOKINE GENES

Stonâns, Ilmars; Stonane, Elita; Rußwurm, Stefan; Deigner, Hans‐Peter; Böhm, Konrad J.; Wiederhold, Matthias; Jäger, Lothar; Reinhart, Konrad

doi:10.1006/cyto.1998.0366

Cited by 42 publications

(23 citation statements)

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“…This in vivo induction of Mrp3 and Lrh-1 was reproduced by Tnf␣ or IL1␤ treatment of HepG2 cells, thus confirming that these changes could be directly mediated by these inflammatory cytokines. While recognizing the fact that HepG2 cells, like primary mouse hepatocytes, may synthesize cytokines (26,27), we would suggest that cytokine protein levels were likely manyfold lower than those used in our experiments. It is important to note that there also appears to be a Tnf␣-dependent posttranslational effect on Lrh-1 protein abundance in vivo.…”

Section: Discussionmentioning

confidence: 88%

Tumor Necrosis Factor α-dependent Up-regulation of Lrh-1 and Mrp3(Abcc3) Reduces Liver Injury in Obstructive Cholestasis

Bohan

Chen

Denson

et al. 2003

Journal of Biological Chemistry

141

136

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Mrp3(Abcc3) is markedly induced following bile duct ligation (BDL) in the rat and in some human cholestatic liver diseases and is believed to ameliorate liver injury in this setting. Recently, the orphan nuclear receptor fetoprotein transcription factor/cholesterol-7␣-hydroxylase promoter factor (CPF/FTF/Lrh-1) has been shown to activate Mrp3 expression. However, whether inflammatory cytokines or elevated bile acid levels increased Lrh-1/Mrp3 expression in obstructive cholestasis was not known. We hypothesized that induction of Mrp3 would be associated with Lrh-1 up-regulation and would require intact cytokine signaling. Male tumor necrosis factor (Tnf) receptor I (Tnfr؊/؊) mice and C57BLJ wild type (WT) controls were subjected to sham surgery or bile duct ligation. HepG2 cells were treated with bile acids or cytokines. Immunoblot assay and real time reverse transcriptase-PCR were used to determine expression of MRP3/Mrp3, CPF/Lrh-1, Mrp2, and Bsep. CPF/ Lrh-1 DNA binding to the MRP3/Mrp3 promoter was assessed using electrophoretic mobility shift assay, and promoter activity was determined by luciferase assay. Total bile acids and lactate dehydrogenase were measured using colorimetric assays, and cytokine abundance was determined by enzyme-linked immunosorbent assay. Lrh-1 and Mrp3 were significantly induced after BDL in WT but not Tnfr؊/؊ mice. This was associated with more severe hepatocellular necrosis in Tnfr؊/؊ mice. Lrh-1 binding to the Mrp3 promoter increased after BDL in WT but not in Tnfr؊/؊ mice. Tnf␣ treatment of HepG2 cells also up-regulated CPF and MRP3, increased CPF binding to the MRP3 promoter, and upregulated MRP3 promoter activity. These results indicate that induction of Mrp3 after BDL is due to Tnf␣-dependent up-regulation of Lrh-1. They provide strong evidence that induction of Mrp3 plays a significant role in hepatocyte protection during obstructive cholestasis.

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Section: Discussionmentioning

confidence: 88%

Tumor Necrosis Factor α-dependent Up-regulation of Lrh-1 and Mrp3(Abcc3) Reduces Liver Injury in Obstructive Cholestasis

Bohan

Chen

Denson

et al. 2003

Journal of Biological Chemistry

141

136

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“…To this end. we cultured the human hepatoma cell line HepG2, which was previously shown to express multiple cytokines genes including TGFb1, 31 in order to obtain significant quantity of CM. As shown in the Supplementary Figure 5, we found that HepG2 secreted good quantities of TGF-b1 in the culture medium, around 200 pg/ml during the first 24 h, that increased to around 1200 pg/ml after 72 h of culture.…”

Section: Tgf-b1 Down-modulate Ncam Expression On Stcsmentioning

confidence: 99%

Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma

Balzarini

Benetti

Invernici

et al. 2012

Laboratory Investigation

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Hepatocellular carcinoma (HCC) is a very angiogenic and malignant cancer. Conventional chemotherapy is poorly effective because of the abnormal structural organization of HCC-infiltrating vessels. In previous work, we demonstrated that HCC angiogenesis is driven by transforming growth factor beta-1(TGF-b1)/CD105 axis, stimulating liver-derived microvascular endothelial cells (Ld-MECs) migration. As TGF-b1 also affects mural cells (MCs) recruitment and maturation, we asked whether it may contribute to HCC-induced vascular abnormalities. HCC and adjacent non-neoplastic liver (nNL) biopsies obtained from 12 patients were analyzed by immunohistochemistry for angiogenic markers CD105, TGF-b1, CD44 and vascular endothelial growth factor-a (VEGFa) and for MC markers NG2, a-smooth muscle actin (aSMA) and neural cell adhesion molecule (NCAM). The same markers were also investigated by immunocytochemistry on cultured HCC-derived stromal cells (HCC-StCs) and nNL-derived StCs (nNL-StCs) isolated from the same liver biopsies. Angiogenic factors released by StCs were analyzed by ELISA and the interaction between StCs and Ld-MECs by adhesion assay. Compared with nNL, HCC biopsies showed increased angiogenic markers and aSMA that was localized in vessels. By contrast, NG2 and NCAM were substantially localized in tumor cells but absent in vessels and stroma. Cultured HCCStCs showed less expression of NG2, aSMA and NCAM. They also demonstrated a lower capacity to release angiogenic factors and adhered on Ld-MECs. HCC-StCs and nNL-StCs treated with TGF-b1 or with of HepG2 (a human hepatoma cell line) derived conditioned medium (CM), down-modulated NCAM expression, whereas anti-NCAM antibodies significantly reduced the adhesion of StCs to Ld-MECs. By further blocking TGF-b1 with anti-TGF-b1 antibodies or with Ly-364947 (a specific inhibitor TGF-b1-receptor) adhesion to Ld-MECs and NCAM expression respectively was partially restored. TGF-b1 contributes to HCC-induced vascular alterations by affecting the interaction between HCC-StCs and Ld-MECs through a down-modulation of NCAM expression. A growing tumor recruits new blood vessels to ensure a sufficient quantity of nutrients and oxygen necessary for cancer cell survival and proliferation.1 During this process, neoformed capillaries undergo abnormal maturation 2 and vascular abnormalities are often observed in tumor, mainly involving either the composition of the basement membrane or mural cells (MCs) content. 3,4 To this regard, pericytes and smooth muscle cells (SMCs) are fundamental to determine an

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“…It has been suggested that hepatocytes themselves may also make cytokines. 50 The responses of hepatocytes to cytokines are outlined in Table 2. With regards to the Th1 type cytokines (IFN-g and IL-12) their effects overall appear to be to improve the ability of the hepatocytes to present antigen, to promote influx of activated lymphocytes through chemokine secretion, and to prime hepatocytes for death through apoptosis.…”

Section: Cytokines and Chemokinesmentioning

confidence: 99%

HCV immunology–Death and the maiden T cell

2003

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Cellular immune responses play an important role in the control of hepatitis C virus (HCV), although in the majority of cases they ultimately fail. We examine the mechanisms by which virus-specific T cells may interact with a cell that is infected with HCV and how this interaction may explain the success and failure of the immune response. As an infected cell presenting foreign antigen, the hepatocyte will interact with a large number of lymphocytes, both by direct cell to cell contact and by indirect means through the secretion of cytokines and chemokines. These interactions may lead on the one hand to the death of infected hepatocytes or suppression of viral replication and on the other hand to the death of T lymphocytes or down regulation of their function. We suggest that activation of lymphocytes in lymphoid organs leads to generation of effector T cells (positive loop), while at the same time presentation of antigen in the liver either on hepatocytes or other specialised antigen presenting cells depresses these responses (negative loop). This model helps to explain both the specific phenotype and low frequencies of HCV specific CTL in chronic infection, through early elimination of cells before expansion and maturation can occur. The outcome of HCV infection is likely to result from the early balance between these two simultaneous loops.

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HepG2 HUMAN HEPATOMA CELLS EXPRESS MULTIPLE CYTOKINE GENES

Cited by 42 publications

References 0 publications

Tumor Necrosis Factor α-dependent Up-regulation of Lrh-1 and Mrp3(Abcc3) Reduces Liver Injury in Obstructive Cholestasis

Tumor Necrosis Factor α-dependent Up-regulation of Lrh-1 and Mrp3(Abcc3) Reduces Liver Injury in Obstructive Cholestasis

Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma

HCV immunology–Death and the maiden T cell

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