title: Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas.
abstract: Malignant mesothelioma (MM), an incurable tumor, is reportedly an interleukin-6 (IL-6) secreting tumor. The pathological significance of IL-6 overexpression in this tumor, however, has remained unclear. We investigated the biological functions of IL-6 in mesotheliomas. Five mesothelioma cell lines were analyzed for IL-6 production and IL-6 receptor (IL-6R) expression. Of them, 2 produced high levels of IL-6, 2 produced intermediate levels and 1 cell line showed no secretion. All mesothelioma cell lines used in this study expressed very small amounts of IL-6R mRNA. We compensated for this low level of IL-6R expression in mesotheliomas by adding recombinant soluble IL-6R (sIL-6R) to mediate the IL-6 signal. IL-6 together with sIL-6R was found to promote cell growth of H2052 and H226 MMs classified as high-level IL-6 producers in a dose-dependent manner. Moreover, a humanized anti-IL-6R antibody (MRA) capable of blocking IL-6 signaling suppressed the cell growth of mesotheliomas induced by IL-6/sIL-6R. These findings demonstrate that IL-6 serves as an autocrine growth factor in the development of mesothelioma. In addition, IL-6/sIL-6R stimulation increased the expression of vascular endothelial growth factor (VEGF) in 4 out of 5 cell lines, and this induction was inhibited by MRA treatment. The involvement of the signal transducer and activator of transcription 3 (STAT3) pathway in both cell growth and VEGF induction by IL-6/sIL-6R was verified by dominant negative STAT3 transduction combined with adenovirus gene-delivery methods. Although IL-6 induces VEGF through the JAK2/STAT3 pathway, anti-VEGF antibody could not inhibit the IL-6-induced cell growth observed in H2052 and H226. We concluded that IL-6-dependent growth does not occur via VEGF induction. These results suggest that treatment with anti-IL-6R antibody may constitute a potential molecular targeting therapy for MMs.
authors.affiliation: Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Adachi
authors.forename: Chieko
authors.initials: C
authors.lastname: Aoki
authors.forename: Naoko
authors.initials: N
authors.lastname: Yoshio-Hoshino
authors.forename: Koichi
authors.initials: K
authors.lastname: Takayama
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nishimoto
mesh_terms: D049109:Cell Proliferation; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D050822:Cytokine Receptor gp130