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Enhanced killing capacity of human Kupffer cells after activation with human granulocyte/macrophage-colony-stimulating factor and interferon γ

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Abstract

In this study we investigated the effect of the cytokines human granulocyte/macrophage-colony-stimulating Factor (hGM-CSF) and interferon γ (IFNγ) on human Kupffer-cell-mediated cytotoxicity against the SW948 coloncarcinoma cell line. Kupffer cells were isolated from small liver wedge biopsies, taken from 14 patient who had had abdominal surgery for colon carcinoma or partial hepatectomy. The cells were incubated with hGM-CSF (100 ng/ml), or with IFNγ (100 U/ml) or with their combination and the perecentage cytotoxicity was determined using a recently described modified assay. Additional experiments were performed with tumour-necrosis-factor-α(TNFα)-sensitive U937 cells as target. The TNFα secretion of Kupffer cells was measured and we evaluated the effect of TNFα on colon tumour targets. We performed human-Kupffer cell-mediated cytotoxicity blocking experiments with anti-TNFα and used paraformaldehydefixed Kupffer cells to demonstrate lysis of TNFα-sensitive WEHI-164 cells and of SW948 cells. The overall cytotoxicity against SW948 caused by unactivated Kupffer cells (n=14), and by Kupffer cells activated with hGM-CSF (n=14), IFNγ (n=6) or their combination (n=6) was respectively: 19.5±2.6%, 25.3±2.9% 41±9.4% and 45.6±8% at E/T=1 and 28.2±2.9%, 35.6±3.2%, 55.6±9.7% and 62.8% at E/T=5. All differences were statistically significant (P<0.05). No growth-promoting activity by hGM-CSF on the SW948 tumour cells was observed. U937 cells were highly susceptible to Kupffer-cell-mediated cytotoxicity. The TNFα secretion by human Kupffer cells increased in parallel to their cytotoxicity after incubation with these cytokines. Soluble TNFα had only a slight anti-proliferative effect on SW948 cells, while specific anti-TNFα blocked Kupffer cell cytotoxicity by up to 80%. Finally, paraformaldehyde-fixed Kupffer cells were able to lyse WEHI-164 and SW948 cells. This indicates that expression of cell-associated TNFα is the main cytolytic mechanism of human-Kupffer-cell-mediated cytotoxicity. The implications for the use of hGM-CSF and IFNγ in vivo are discussed.

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Authors and Affiliations

  1. Department of Surgical Oncology, Free University Hospital, Amsterdam, The Netherlands

    B. Schuurman, G. Heuff & S. Meyer

  2. Department of Cell Biology, Free University Hospital, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    R. H. J. Beelen

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  1. B. Schuurman
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  2. G. Heuff
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  3. R. H. J. Beelen
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  4. S. Meyer
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Schuurman, B., Heuff, G., Beelen, R.H.J. et al. Enhanced killing capacity of human Kupffer cells after activation with human granulocyte/macrophage-colony-stimulating factor and interferon γ. Cancer Immunol Immunother 39, 179–184 (1994). https://doi.org/10.1007/BF01533384

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  • DOI: https://doi.org/10.1007/BF01533384

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