Novel insights into IL-6 cis- and trans-signaling pathways by differentially manipulating the assembly of the IL-6 signaling complex

Marine Lacroix, François Rousseau, Florence Guilhot, Pauline Malinge, Giovanni Magistrelli, Suzanne Herren, Simon Arnett Jones, Gareth Wyn Jones, Jürgen Scheller, Rami Lissilaa, Marie Kosco-Vilbois, Zoë Johnson, Vanessa Buatois, Walter Ferlin

Research output: Contribution to journalArticle (Academic Journal)

Abstract

The IL-6 signaling complex is described as a hexamer, formed by the association of two IL-6/IL-6R/gp130 trimers, with gp130 being the signal transducer inducing cis- and trans-mediated signaling via a membrane-bound (mb) or soluble (s) form of the IL-6R, respectively. 25F10 is an anti-mouse IL-6R mAb that binds to both mbIL-6R and sIL-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 yet 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 to 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 which should be taken into account when developing strategies to inhibit IL-6 clinically.
Original languageUndefined/Unknown
Pages (from-to)26943-26953
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Early online date11 Sep 2015
DOIs
Publication statusPublished - 6 Nov 2015

Cite this

Lacroix, M., Rousseau, F., Guilhot, F., Malinge, P., Magistrelli, G., Herren, S., Jones, S. A., Jones, G. W., Scheller, J., Lissilaa, R., Kosco-Vilbois, M., Johnson, Z., Buatois, V., & Ferlin, W. (2015). Novel insights into IL-6 cis- and trans-signaling pathways by differentially manipulating the assembly of the IL-6 signaling complex. Journal of Biological Chemistry, 290, 26943-26953. https://doi.org/10.1074/jbc.M115.682138