Novel Insights into Interleukin 6 (IL-6) Cis- and Trans-signaling Pathways by Differentially Manipulating the Assembly of the IL-6 Signaling Complex

  • J Biol Chem. 2015 Nov 6;290(45):26943-26953. doi: 10.1074/jbc.M115.682138.
Marine Lacroix  1 ,  François Rousseau  1 ,  Florence Guilhot  1 ,  Pauline Malinge  1 ,  Giovanni Magistrelli  1 ,  Suzanne Herren  1 ,  Simon A Jones  2 ,  Gareth W Jones  2 ,  Jürgen Scheller  3 ,  Rami Lissilaa  4 ,  Marie Kosco-Vilbois  1 ,  Zoë Johnson  1 ,  Vanessa Buatois  1 ,  Walter Ferlin  5
Affiliations
  • 1. Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland.
  • 2. Cardiff Institute of Infection and Immunity, The School of Medicine, Cardiff University, Heath Campus, Cardiff CF14 4XN, United Kingdom.
  • 3. Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
  • 4. Glenmark Pharmaceuticals SA, 2300 La Chaux-De-Fonds, Switzerland.
  • 5. Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland. Electronic address: [email protected].
PMID: 26363066 DOI: 10.1074/jbc.M115.682138
Abstract

The IL-6 signaling complex is described as a hexamer, formed by the association of two IL-6·IL-6 receptor (IL-6R)·gp130 trimers, with gp130 being the signal transducer inducing cis- and trans-mediated signaling via a membrane-bound or soluble form of the IL-6R, respectively. 25F10 is an anti-mouse IL-6R mAb that binds to both membrane-bound IL-6R and soluble IL-6R with the unique property of specifically inhibiting trans-mediated signaling events. In this study, epitope mapping revealed that 25F10 interacts at site IIb of IL-6R but allows the binding of IL-6 to the IL-6R and the recruitment of gp130, forming a trimer complex. Binding of 25F10 to IL-6R prevented the formation of the hexameric complex obligate for trans-mediated signaling, suggesting that the cis- and trans-modes of IL-6 signaling adopt different mechanisms for receptor complex assembly. To study this phenomenon also in the human system, we developed NI-1201, a mAb that targets, in the human IL-6R sequence, the epitope recognized by 25F10 for mice. Interestingly, NI-1201, however, did not selectively inhibit human IL-6 trans-signaling, although both mAbs produced beneficial outcomes in conditions of exacerbated IL-6 as compared with a site I-directed mAb. These findings shed light on the complexity of IL-6 signaling. First, triggering cis- versus trans-mediated IL-6 signaling occurs via distinctive mechanisms for receptor complex assembly in mice. Second, the formation of the receptor complex leading to cis- and trans-signaling biology in mice and humans is different, and this should be taken into account when developing strategies to inhibit IL-6 clinically.

Keywords
antibody; complex; interleukin 6 (IL-6); receptor; signaling.
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