Interleukin‐6 signal transducer gp130 has specific binding sites for different cytokines as determined by antagonistic and agonistic anti‐gp130 monoclonal antibodies

Wijdenes, John; Heinrich, Peter C.; Müller‐Newen, Gerhard; Roche, Catherine; Gu, Zhifeng; Clément, Claude; Klein, Bernard

doi:10.1002/eji.1830251240

Cited by 86 publications

(105 citation statements)

References 32 publications

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“…23 However, we have identified a pair of mAb able to induce gp130 dimerization and gp130-mediated signaling. 24 We report here that these mAb can induce gp130-mediated signal transduction in myeloma cells, support the long-term survival and growth of all our IL-6-dependent myeloma cell lines, support the survival of primary myeloma cells and make it possible to obtain anti-gp130 mAb-dependent myeloma cell lines from patients with secondary extramedullary proliferation.…”

Section: Introductionsupporting

confidence: 52%

Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors

Vos

Rebouissou³

et al. 2000

Leukemia

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We have previously reported obtaining two monoclonal antibodies (mAb) against the human gp130 interleukin-6 (IL-6) transducer which made possible the dimerization of gp130 and the activation of several IL-6-driven functions when used together. We report here that these mAb induce gp130-mediated signaling in human myeloma cells and support the survival and the long-term growth of five IL-6-dependent human myeloma cell lines. Their agonist activity is not affected by neutralizing antibodies to IL-6 or IL-6R. These mAb induce a transient proliferation of primary myeloma cells from most patients with multiple myeloma. Again, IL-6 inhibitors do not affect this agonist activity. By using highly purified primary myeloma cells, we found that these anti-gp130 mAb supported the long-term survival of primary myeloma cells from five patients with primary plasma cell leukemia but failed to induce their long-term growth. For patients with fulminant disease and secondary extramedullary proliferation, the antibodies supported a long-term survival and growth, and anti-gp130 mAbdependent cell lines were obtained. For patients with medullary involvement only, a co-stimulatory signal is necessary, together with gp130 activation, to trigger cell survival and cycling. Leukemia (2000) 14, 188-197.

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Section: Introductionsupporting

confidence: 52%

Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors

Vos

Rebouissou³

et al. 2000

Leukemia

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“…The total loss of activity of ⌬5 is not due to participation of D5 in the Ab epitope because this deletion mutant is recognized by both agonistic Abs in FACS analysis. Furthermore, in a previous study the epitopes of the agonistic Abs were mapped to the membranedistal part of gp130 (26). Thus, there seems to exist an absolute requirement for domain 5 to achieve activation of gp130.…”

Section: Discussionmentioning

confidence: 94%

“…Soluble IL-6R (sIL-6R) (24), soluble gp130 (25), as well as soluble IL-11R (16) were expressed in insect cells as described previously. The monoclonal gp130 Abs B-R3, B-S12-G7, B-P4, and B-P8 were generated as described previously (26). All other Abs were purchased from Dako (Hamburg, Germany).…”

Section: Enzymes Proteins Abs Chemicals and Cell Culturementioning

confidence: 99%

“…Some of these Abs act agonistically, such as the combination of B-S12 and B-P8, while others, such as B-R3, were neutralizing (26). The mAb B-P4 has been described to specifically inhibit IL-11 (26) and, depending on the cells investigated, IL-6 responses (33). The antagonistic mAbs B-P4 and B-R3 were used as precipitating Abs in a ternary complex formation assay.…”

Section: The Il-6 and Il-11 Neutralizing Gp130 Mab B-p4 Maps To The Mmentioning

confidence: 99%

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Importance of the Membrane-Proximal Extracellular Domains for Activation of the Signal Transducer Glycoprotein 130

Kurth

Horsten

Pflanz

et al. 2000

The Journal of Immunology

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The transmembrane glycoprotein gp130 is the common signal transducing receptor subunit of the IL-6-type cytokines. The gp130 extracellular part is predicted to consist of six individual domains. Whereas the role of the three membrane-distal domains (D1–D3) in binding of IL-6 and IL-11 is well established, the function of the membrane-proximal domains (D4–D6) is unclear. Mapping of a neutralizing mAb to the membrane-proximal part of gp130 suggests a functional role of D4–D6 in receptor activation. Individual deletion of these three domains differentially interferes with ligand binding of the soluble and membrane-bound receptors. All deletion mutants do not signal in response to IL-6 and IL-11. The deletion mutants Δ4 and, to a lesser extent, Δ6 are still activated by agonistic monoclonal gp130 Abs, whereas the deletion mutant Δ5 does not respond. Because membrane-bound Δ5 binds IL-6/soluble IL-6R as does wild-type gp130, but does not transduce a signal in response to various stimuli, this domain plays a prominent role in coupling of ligand binding and signal transduction. Replacement of the fifth domain of gp130 by the corresponding domain of the homologous G-CSF receptor leads to constitutive activation of the chimera upon overexpression in COS-7 cells. In HepG2 cells this mutant responds to IL-6 comparable to wild-type gp130. Our findings suggest a functional role of the membrane-proximal domains of gp130 in receptor activation. Thus, within the hematopoietic receptor family the mechanism of receptor activation critically depends on the architecture of the receptor ectodomain.

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“…Soluble IL-6R was prepared as described previously (17). The monoclonal gp130 Ab B-P4 was generated as described elsewhere (18). All other Abs were purchased from Dako (Hamburg, Germany).…”

Section: Enzymes Proteins Abs Chemicals and Cell Culturementioning

confidence: 99%

Two Different Epitopes of the Signal Transducer gp130 Sequentially Cooperate on IL-6-Induced Receptor Activation

Pflanz

Kurth

Grötzinger

et al. 2000

The Journal of Immunology

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Cytokines are key mediators for the regulation of hemopoiesis and the coordination of immune responses. They exert their various functions through activation of specific cell surface receptors, thereby initiating intracellular signal transduction cascades which lead to defined cellular responses. As the common signal-transducing receptor subunit of at least seven different cytokines, gp130 is an important member of the family of hemopoietic cytokine receptors which are characterized by the presence of at least one cytokine-binding module. Mutants of gp130 that either lack the Ig-like domain D1 (ΔD1) or contain a distinct mutation (F191E) within the cytokine-binding module have been shown to be severely impaired with respect to IL-6 induced signal transduction. After cotransfection of COS-7 cells with a combination of both inactive gp130 mutants, signal transduction in response to IL-6 is restored. Whereas cells transfected with ΔD1 do not bind IL-6/sIL-6R complexes, cells transfected with the F191E mutant bind IL-6/sIL-6R with low affinity. Combination of ΔD1 and F191E, however, leads to high-affinity ligand binding. These data suggest that two different gp130 epitopes, one on each receptor chain, sequentially cooperate in asymmetrical binding of IL-6/IL-6R in a tetrameric signaling complex. On the basis of our data, a model for the mechanism of IL-6-induced gp130 activation is proposed.

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Interleukin‐6 signal transducer gp130 has specific binding sites for different cytokines as determined by antagonistic and agonistic anti‐gp130 monoclonal antibodies

Cited by 86 publications

References 32 publications

Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors

Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors

Importance of the Membrane-Proximal Extracellular Domains for Activation of the Signal Transducer Glycoprotein 130

Two Different Epitopes of the Signal Transducer gp130 Sequentially Cooperate on IL-6-Induced Receptor Activation

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