Abstract
Activation of the signaling transduction pathways mediated by oncostatin M (OSM) requires the binding of the cytokine to either type I OSM receptor (leukemia inhibitory factor receptor/gp130) or to type II OSM receptor (OSMR/gp130). In the present work we have developed an enzyme-linked immunosorbent assay detecting a soluble form of OSMR (sOSMR) secreted by glioblastoma, hepatoma, and melanoma tumor cell lines. sOSMR was also present in sera of healthy individuals, with increased levels in multiple myeloma. Molecular cloning of a corresponding cDNA was carried out, and it encoded for a 70-kDa protein consisting of a half cytokine binding domain containing the canonical WSXWS motif, an immunoglobulin-like domain, and the first half of a second cytokine binding domain with cysteines in fixed positions. Analysis of the soluble receptor distribution revealed a preferential expression in lung, liver, pancreas, and placenta. sOSMR was able to bind OSM and interleukin-31 when associated to soluble gp130 or soluble interleukin-31R, respectively, and to neutralize both cytokine properties. We have also shown that OSM could positively regulate the synthesis of its own soluble receptor in tumor cells.
Highlights
The cytokines of the IL-6 family use two- or three-membrane subunit receptors to form high affinity receptor complexes able to mediate downstream signaling events (13–14)
We looked for a native form of soluble form of OSMR (sOSMR) by screening culture supernatant from different cell lines
We could not observe the secretion of sOSMR in neuroblastoma, choriocarcinoma, and lymphocyte-derived cell lines
Summary
The cytokines of the IL-6 family use two- or three-membrane subunit receptors to form high affinity receptor complexes able to mediate downstream signaling events (13–14). Soluble OSMR Expression and Binding of OSM to sgp130sOSMR Complex—The sOSMR was expressed as a tagged protein (V5-histidine tags) and purified by affinity from culture supernatants of stably transfected cells (Fig. 6A). A 50% inhibition of the signal was measured when sOSMR and sgp130 were added together to the type I or type II OSM receptor-expressing BAF/3 cell cultures (Fig. 9, C and D).
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