Interleukin-6 involvement in mesothelioma pathobiology: inhibition by interferon alpha immunotherapy

Our plain-English summary of Interleukin-6 involvement in mesothelioma pathobiology: inhibition by interferon alpha immunotherapy, by H. Bielefeldt-Ohmann, A.L. Marzo, R.P. Himbeck, et al (Cancer Immunology, Immunotherapy, 1995).

The study

• Authors: H. Bielefeldt-Ohmann, A.L. Marzo, R.P. Himbeck, A.G. Jarnicki, B.W. Robinson, D.R. Fitzpatrick
• Journal: Cancer Immunology, Immunotherapy
• Published: 1995;40(4):241-50
• Cited by: 44 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

A role for interleukin-6 (IL-6) in malignant mesothelioma has been suggested by the clinically presenting symptoms of mesothelioma patients, which include fever, weight loss and thrombocytosis. A murine model of malignant mesothelioma was therefore used to examine the potential role of IL-6 in this cancer type and whether the effect of interferon alpha (IFN alpha) therapy on mesothelioma might be mediated, in part, by regulating IL-6 levels and/or IL-6-induced pathobiology. A panel of human and murine mesothelioma cell lines was assayed for endogenous IL-6 production in a bioassay, and for IL-6-mRNA expression. Four out of 5 human and 5 out of 15 murine mesothelioma cell lines produced moderate to high levels of bioactive IL-6 in vitro. This result was corroborated by mRNA detection. One of the representative murine cell lines, AB22, was chosen for further in vivo studies in the murine mesothelioma model. In AB22-inoculated mice detectable serum IL-6 levels were found to precede macroscopically detectable tumour growth, clinical signs (cachexia, abdominal distension, diarrhoea) and changes in the peripheral lymphoid organs (cell depletion and functional depression). Treatment with anti-IL-6 antibody curtailed the clinical symptoms (P < 0.001), as did treatment with recombinant human (rhu) IFN alpha (P < 0.001). Neither anti-IL-6 antibody nor rhuIFN alpha had a direct growth-inhibitory effect on the AB22 mesothelioma cell line in vitro, however, in vivo rhuIFN alpha treatment of mice inoculated with AB22 cells attenuated both IL-6 mRNA expression in the tumours and serum IL-6 levels, ameliorated the depression of lymphocyte activities, and enhanced the number of tumour-infiltrating lymphocytes and macrophages. On the basis of these results it is suggested that IL-6 mediates some of these effects, directly or indirectly, and that a combination therapy of rhuIFN alpha and anti-IL-6 antibody may be an improved palliative treatment for patients with malignant mesothelioma.

In plain English

This laboratory and animal study, from the University of Western Australia, asked whether interleukin-6 (IL-6), a signalling protein made by cells, plays a part in malignant mesothelioma. It also asked whether interferon alpha treatment works partly by lowering IL-6. Asbestos exposure itself was not studied. In culture, 5 of 6 human and 5 of 11 mouse mesothelioma cell lines produced measurable IL-6. Female mice were injected in the abdomen with AB22, a mouse mesothelioma cell line that produces IL-6. High blood IL-6 levels appeared before visible tumours and before symptoms. An antibody against IL-6 delayed the onset of symptoms and slowed the clinical course (P < 0.001). Compared with placebo, daily recombinant human interferon alpha lengthened the disease course (P = 0.014) and improved survival (P < 0.001). It also lowered blood IL-6, reduced IL-6 gene activity in tumours, and improved the responses of spleen immune cells. The authors concluded that high IL-6 was associated with wasting and liver damage in the mice. They suggested that combining interferon alpha with anti-IL-6 antibody could be a treatment approach for human disease. The authors noted that some blood IL-6 comparisons came from a small number of animals.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of human and mouse mesothelioma cell lines combined with animal experiments in a mouse model of mesothelioma
• Who was studied: Six human and eleven mouse mesothelioma cell lines in culture. Female BALB/c mice, 6-8 weeks old, obtained in Western Australia, were injected into the abdominal cavity (intraperitoneally) with the AB22 mouse mesothelioma cell line.
• Exposure: No asbestos or fiber exposure was studied. Mice were injected with AB22 mesothelioma cells. They were treated with a rat anti-mouse IL-6 antibody (1 mg per mouse twice weekly) or with recombinant human interferon alpha hybrids (B/D or A/D, 1 x 10^5 units per mouse daily). Control animals received placebo (diluent only) or normal rat serum.
• Main results:
  • In culture, 5 of 6 human mesothelioma cell lines and 5 of 11 mouse mesothelioma cell lines produced detectable bioactive IL-6.
  • In mice injected with AB22 cells, high serum IL-6 levels came before clinical symptoms and before visible tumour growth.
  • In AB22-injected mice, twice-weekly anti-IL-6 antibody treatment starting on the day of tumour cell challenge delayed the onset of clinical symptoms and slowed the clinical course (P < 0.001). Control rat serum had no effect.
  • Mice challenged with AB22 cells and treated daily with interferon alpha B/D from day 6 had a longer disease course (P = 0.014) and improved survival (P < 0.001) compared with placebo-treated mice.
  • In this interferon B/D experiment, mean serum IL-6 was 7.3 plus or minus 3.8 U/ml in 3 interferon-treated mice and 49.2 plus or minus 23.6 U/ml in 6 placebo-treated mice.
  • In a repeat experiment with interferon alpha A/D, 7 of 10 placebo-treated mice were killed on day 12 for severe cachexia. Five randomly selected interferon-treated mice (from 15) killed at the same time showed no tumour growth or organ pathology, and they had significantly lower serum IL-6 than placebo-treated mice (P < 0.05).
  • Interferon alpha treatment reduced IL-6 mRNA expression in the tumours. Tumours from treated mice had more CD5+ and CD4+ tumour-infiltrating lymphocytes and more F4/80+ macrophage-like cells.
  • Spleen cells from interferon-treated mice were more responsive to mitogens and produced more cytokines than cells from placebo-treated mice.
  • Adding IL-6 or blocking it had no apparent effect on the growth of AB22 cells or the other mesothelioma cell lines tested in culture.
• The authors' conclusion: The authors concluded that high serum IL-6 was associated with cachexia and liver damage in this mouse model, and that these effects could be curtailed by anti-IL-6 antibody. They suggested that, for the human disease, a combined therapeutic and palliative approach using interferon alpha together with anti-IL-6 antibody could be designed.
• Limitations the authors state:
  • The serum IL-6 comparison in the interferon B/D experiment was tested in only a small number of animals.
  • The authors stated that it is not yet known whether the improvement in immune depression with interferon is a direct effect, a result of reduced tumour development, or some other effect.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Immunotherapy, Malignant Mesothelioma, Cachexia, Tumor-Infiltrating Lymphocytes, Macrophage, Palliative Care.

Related studies

• Potential for interferon-alpha-based therapy in mesothelioma: assessment in a murine model — H. Bielefeldt-Ohmann, D.R. Fitzpatrick, et al. (1995)
• Interferon-alpha and -gamma in combination with chemotherapeutic drugs: in vitro sensitivity studies in four human mesothelioma cell lines — A.M. Hand, K. Husgafvel-Pursiainen, et al. (1992)
• Safety, feasibility and therapeutic activity of intrapleural autologous lymphocyte conditioned medium followed by systemic recombinant interleukin-2 and interferon-alpha in a patient with malignant pleural mesothelioma — S. Duensing, H. Hamm, et al. (1997)
• Endogenous retrovirus expression activates type-I interferon signaling in an experimental mouse model of mesothelioma development — S. Sun, F. Frontini, et al. (2021)
• Interleukin-6 as a therapeutic target in candidate inflammatory diseases — N. Nishimoto (2010)
• Interferon (IFN)-alpha and IFN-gamma in combination with methotrexate: in vitro sensitivity studies in four human mesothelioma cell lines — A. Hand, K. Pelin, et al. (1995)

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