title: Novel Insights into Interleukin 6 (IL-6) Cis- and Trans-signaling Pathways by Differentially Manipulating the Assembly of the IL-6 Signaling Complex.
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.
authors.affiliation: Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: Marine
authors.initials: M
authors.lastname: Lacroix
authors.affiliation: Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Guilhot
authors.affiliation: Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: Pauline
authors.initials: P
authors.lastname: Malinge
authors.affiliation: Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Magistrelli
authors.affiliation: Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Herren
authors.affiliation: Cardiff Institute of Infection and Immunity, The School of Medicine, Cardiff University, Heath Campus, Cardiff CF14 4XN, United Kingdom.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Cardiff Institute of Infection and Immunity, The School of Medicine, Cardiff University, Heath Campus, Cardiff CF14 4XN, United Kingdom.
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Jones
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.affiliation: Glenmark Pharmaceuticals SA, 2300 La Chaux-De-Fonds, Switzerland.
authors.forename: Rami
authors.initials: R
authors.lastname: Lissilaa
authors.affiliation: Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Kosco-Vilbois
authors.affiliation: Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Johnson
authors.affiliation: Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Buatois
authors.affiliation: Novimmune SA Novimmune SA, 1228 Plan-les-Ouates, Switzerland. Electronic address: wferlin@novimmune.com.
authors.forename: Walter
authors.initials: W
authors.lastname: Ferlin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D050822:Cytokine Receptor gp130 / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005816:Genetic Complementation Test; D006801:Humans; D015850:Interleukin-6 / Q000737:chemistry* / Q000172:deficiency / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D051381:Rats; D019947:Receptors, Interleukin-6 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; C508600:IL6 protein, human; C508603:IL6R protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D046912:Multiprotein Complexes; D019947:Receptors, Interleukin-6; C577686:interleukin-6, mouse; D050822:Cytokine Receptor gp130
keywords: antibody; complex; interleukin 6 (IL-6); receptor; signaling