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.