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Interleukin-6 involvement in mesothelioma pathobiology: inhibition by interferon alpha immunotherapy
H Bielefeldt-Ohmann1, A L Marzo, R P Himbeck
1University of Western Australia Department of Medicine, Queen Elizabeth II Medical Centre, Nedlands.
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.
Insights
Interleukin-6 (IL-6) plays a role in malignant mesothelioma. Interferon alpha (IFN alpha) therapy may work by regulating IL-6, suggesting combination therapy for improved palliative treatment.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Malignant mesothelioma symptoms like fever and weight loss suggest a role for interleukin-6 (IL-6).
- Interferon alpha (IFN alpha) is a potential therapy, but its mechanism in mesothelioma, possibly involving IL-6, needs investigation.
Purpose of the Study:
- To investigate the role of IL-6 in malignant mesothelioma.
- To determine if IFN alpha therapy's effects are mediated by IL-6 regulation.
- To explore combination therapy potential.
Main Methods:
- Assayed human and murine mesothelioma cell lines for IL-6 production and mRNA expression.
- Utilized a murine mesothelioma model (AB22 cell line) for in vivo studies.
- Administered anti-IL-6 antibody and recombinant human IFN alpha (rhuIFN alpha) to evaluate therapeutic effects.
Main Results:
- Multiple mesothelioma cell lines produced bioactive IL-6 in vitro.
- In vivo, elevated serum IL-6 preceded tumor growth and clinical signs.
- Both anti-IL-6 antibody and rhuIFN alpha treatment reduced clinical symptoms.
- rhuIFN alpha in vivo attenuated IL-6 expression, improved lymphocyte activity, and increased immune cell infiltration.
Conclusions:
- IL-6 contributes to malignant mesothelioma progression and associated symptoms.
- IFN alpha therapy impacts mesothelioma by modulating IL-6 levels and the tumor microenvironment.
- Combination therapy with rhuIFN alpha and anti-IL-6 antibody shows promise for improved palliative treatment in malignant mesothelioma.