Production of interleukin‐1β and interleukin‐6 in hepatoblastoma

Schweinitz, Dietrich von; Hadam, M.; Welte, Karl; Mildenberger, H; Pietsch, Torsten

doi:10.1002/ijc.2910530504

Cited by 35 publications

(17 citation statements)

References 20 publications

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“…The exact mechanism of this hematologic complication, however, remains unclear. Schweinitz et al [5] have suggested interleukin 6 (IL-6) to be one of the mediators showing that hepatoblastoma cells induce IL-6 production in surrounding fibroblasts and endothelial cells by virtue of the endogenous secretion of IL-1β. Recently, however, the major physiological regulator of thrombopoiesis has been purified as c-mpl ligand and termed thrombopoietin (TPO) [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Thrombopoietin in Patients with Hepatoblastoma

et al. 1998

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Marked thrombocytosis (over 50 × 10 4 /µl) is frequently seen in patients with hepatoblastoma. Thrombopoietin (TPO), c-mpl ligand, has recently been purified as the major physiological regulator of the thrombopoiesis and is mainly produced in the liver. Since it is possible that TPO participates in thrombocytosis and the tumor growth of this particular hepatic tumor, serum TPO levels in addition to interleukin 1β (IL-1β) and IL-6 levels were assessed in seven untreated patients by using a sandwich enzymelinked immunosorbent assay. High serum TPO levels were observed in all of the examined patients. The level ranged from 3.15 to 11.02 (mean ± standard deviation; 6.08 ± 1.25) fmol/ml. IL-6 levels were also somewhat higher than normal. Platelet counts, however, appeared to correlate more with serum TPO levels (p = 0.1) than with IL-1β (p = 0.5) and IL-6 (p = 0.2) levels. Furthermore, using the reverse transcriptase polymerase chain reaction method, the expression of c-mpl mRNA was found in five of eight hepatoblastoma tissues as well as TPO mRNA in all eight tissues. These observations suggest that thrombocytosis in hepatoblastoma patients results from the production of cytokine members, including TPO, within tumor tissues. Additionally, it is possible that TPO might act as a type of autocrine and/or paracrine system for cellular growth in this tumor. Stem

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Section: Introductionmentioning

confidence: 99%

Thrombopoietin in Patients with Hepatoblastoma

et al. 1998

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“…Clinical data indicated that a variety of proinflammatory cytokines, including IL-1␤, IL-6, and TNF-␣, were significantly elevated in the serum or within the liver of patients with hepatitis virus infection (19 -21), liver cancer (22), or alcoholic liver diseases (23)(24)(25)(26)(27). We hypothesized that these elevated proinflammatory cytokines (such as IL-1␤) may also regulate IFN signaling pathway and may be implicated in the IFN resistance.…”

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confidence: 99%

IL-1β Attenuates IFN-αβ-Induced Antiviral Activity and STAT1 Activation in the Liver: Involvement of Proteasome-Dependent Pathway

Tian

Shen

Hong

et al. 2000

The Journal of Immunology

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IFN-αβ is the only established treatment for viral hepatitis; however, more than 60% of patients are poorly responsive. Because viral hepatitis is associated with inflammation, we hypothesized that inflammation may attenuate the efficacy of IFN therapy. To test this hypothesis, the effect of IL-1β, one of the major proinflammatory cytokines, on IFN signaling pathway in the liver was examined. Administration of IL-1β in vivo attenuated IFN-αβ-induced STAT1 tyrosine phosphorylation in the liver but not in the spleen. The inhibitory action of IL-1β in vivo was not affected by depleting hepatic Kupffer cells, suggesting that IL-1β may directly target IFN-αβ signaling in hepatocytes. Indeed, pretreatment of human hepatocellular carcinoma HepG2 cells with IL-1β suppressed IFN-αβ-induced antiviral activity and antiviral protein MxA mRNA expression. Furthermore, IL-1β attenuated IFN-αβ-induced STAT1 binding and tyrosine phosphorylation without affecting the level of STAT1 protein. This inhibitory effect can be reversed by pretreatment with either proteasome inhibitors or transfection of dominant negative NF-κB inducing kinase mutants. Taken together, these findings suggest that IL-1β attenuates IFN-αβ-induced STAT1 activation by a proteasome-dependent mechanism. In view of high levels of IL-1β in the serum or within the liver of patients with chronic liver diseases, attenuation of IFN-αβ signaling in the liver by IL-1β could be one of the mechanisms underlying the resistance to IFN therapy in chronic hepatitis C, and IL-1β could be a potential therapeutic target for improving the efficacy of IFN therapy.

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“…This discrepancy as compared with the other hepatoblastoma cells could be explained by the poorly differentiated phenotype of the HepT1 cells, which either inhibited HGF-SF secretion or bound large amounts of the factor, preventing its detection. We have shown that IL-6 is produced in hepatoblastomas by stromal cells under the influence of tumor-cell derived IL-1␤ (von Schweinitz et al, 1993), which was found to activate fibroblasts to secrete HGF-SF (Tamura et al, 1993). In our experiments, IL-1 could have been responsible in part for the activation of fibroblasts to produce the factor.…”

Section: Discussionmentioning

confidence: 99%

“…Primary tumor cell cultures were set up from fresh material of non-pre-treated hepatoblastomas, as described (von Schweinitz et al, 1993). Briefly, tumor pieces were finely minced and incubated with RPMI-1640 medium, 10% FCS and collagenase type B (200 U/ml; GIBCO) for 2 hr.…”

Section: Cell Culturesmentioning

confidence: 99%

Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma

et al. 2000

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Rapid growth of residual tumor after partial hepatectomy has been observed during the period of liver regeneration in children with malignant embryonal hepatoblastoma. The aim of this study was to elucidate the role of hepatocyte growthfactor-scatter factor (HGF-SF) in this phenomenon. Markedly increased serum levels of HGF-SF up to 15 ng/ml were found in 13/18 patients after liver resection and in 6/16 patients with regressive tumors after chemotherapy, in comparison with 15 patients with non-pre-treated hepatoblastoma and 20 healthy children of the same age group. In the tumors, epithelial tumor cells highly expressed the HGF-SF receptor c-met, as shown by immunohistochemistry and m-RNA RT-PCR. The hepatoblastoma cell lines HepT1, HepT3 and HUH6 reacted with significantly increased proliferation to rhHGF-SF in these concentrations (1-15 ng/ml). In the tumors, HGF-SF was found to be expressed in the stromal fibroblasts. In culture, hepatoblastoma cells (HepT3, HUH6) stimulated secretion of the factor by human fibroblasts, indicating the paracrine fashion of intratumoral HGF-SF production. Cultured hepatoblastoma cells ceased to proliferate at 20-50 ng/ml HGF-SF, and they underwent cell death at H100 ng/ml. In contrast, the hepatocellular-carcinoma cell line HepG2 decreased growth under HGF-SF in a dosedependent manner. We conclude that post-operatively secreted and intratumorally produced HGF-SF can function as a growth factor for hepatoblastoma, while the same agent has a cytostatic effect in unphysiologically high concentrations. Int. J. Cancer 85:151-159, 2000.2000 Wiley-Liss, Inc.

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Production of interleukin‐1β and interleukin‐6 in hepatoblastoma

Cited by 35 publications

References 20 publications

Thrombopoietin in Patients with Hepatoblastoma

Thrombopoietin in Patients with Hepatoblastoma

IL-1β Attenuates IFN-αβ-Induced Antiviral Activity and STAT1 Activation in the Liver: Involvement of Proteasome-Dependent Pathway

Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma

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