title: Interleukin-6 involvement in mesothelioma pathobiology: inhibition by interferon alpha immunotherapy.
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.
authors.affiliation: University of Western Australia Department of Medicine, Queen Elizabeth II Medical Centre, Nedlands.
authors.forename: H
authors.initials: H
authors.lastname: Bielefeldt-Ohmann
authors.forename: A L
authors.initials: AL
authors.lastname: Marzo
authors.forename: R P
authors.initials: RP
authors.lastname: Himbeck
authors.forename: A G
authors.initials: AG
authors.lastname: Jarnicki
authors.forename: B W
authors.initials: BW
authors.lastname: Robinson
authors.forename: D R
authors.initials: DR
authors.lastname: Fitzpatrick
mesh_terms: D000818:Animals; D001483:Base Sequence; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007370:Interferon Type I / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D008654:Mesothelioma / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
chemical_list: D007370:Interferon Type I; D015850:Interleukin-6; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000093242:Interleukin-6 Inhibitors