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

Lacroix, Marine, Rousseau, François, Guilhot, Florence, Malinge, Pauline, Magistrelli, Giovanni, Herren, Suzanne, Jones, Simon Arnett ORCID:, Jones, Gareth Wyn, Scheller, Jürgen, Lissilaa, Rami, Kosco-Vilbois, Marie, Johnson, Zoë, Buatois, Vanessa and Ferlin, Walter 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 , pp. 26943-26953. 10.1074/jbc.M115.682138

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Funders: Arthritis Research UK
Date of Acceptance: 2015
Last Modified: 16 Dec 2023 15:44

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