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Interleukin-6 signal transducer gp130 mediates oncostatin M signaling
1Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
Abstract:
Oncostatin M (OM) is a multifunctional cytokine that is structurally and functionally related to interleukin 6 (IL-6) and leukemia inhibitory factor (LIF). The specific receptor for OM has been demonstrated (by chemical cross-linking) to be a 150-kDa protein in a number of cell lines. The IL-6 signal transducer, gp130, is also an affinity converter for the LIF receptor. It does not bind to either IL-6 or LIF, but associates with the alpha subunits of the receptors and transduces the signals. We examined the possible involvement of gp130 in OM binding and signaling. We demonstrate that: (a) anti-gp130 monoclonal antibodies (mAbs) block the inhibitory effect of OM on A375 cell growth, (b) the binding and cross-linking of 125I-OM to H2981 cells are completely abolished by anti-gp130 mAbs, (c) the cross-linked OM-receptor complex is immunoprecipitated by anti-gp130 mAbs, and (d) COS-7 cells transfected with the full-length cDNA encoding gp130 exhibit increased OM binding and cross-linking, which are also blocked by anti-gp130 mAbs. Therefore, we conclude that the 150-kDa OM binding protein previously characterized in a variety of cell lines is gp130. OM is the natural ligand for gp130 and gp130 mediates the biological responses of OM.
Insights
Oncostatin M (OM) binds to gp130, a protein previously thought to only interact with IL-6 and LIF. This study confirms gp130 mediates OM
Area of Science:
- Cytokine biology
- Cell signaling
- Molecular immunology
Background:
- Oncostatin M (OM) is a cytokine related to IL-6 and LIF.
- A 150-kDa protein was previously identified as the specific OM receptor.
- gp130 acts as a signal transducer for LIF receptors.
Purpose of the Study:
- To investigate the role of gp130 in Oncostatin M (OM) binding and signaling.
- To determine if gp130 is the specific receptor for OM.
Main Methods:
- Using anti-gp130 monoclonal antibodies (mAbs) to block OM effects.
- Performing 125I-OM binding and cross-linking studies on cell lines.
- Immunoprecipitation of OM-receptor complexes.
- Transfecting COS-7 cells with gp130 cDNA.
Main Results:
- Anti-gp130 mAbs inhibited OM's effect on A375 cell growth.
- Anti-gp130 mAbs abolished OM binding and cross-linking to H2981 cells.
- The OM-receptor complex was immunoprecipitated by anti-gp130 mAbs.
- gp130-transfected cells showed increased OM binding, blocked by anti-gp130 mAbs.
Conclusions:
- The 150-kDa OM binding protein is gp130.
- OM is the natural ligand for gp130.
- gp130 mediates the biological responses to OM.