Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas

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.