title: Although IL-6 trans-signaling is sufficient to drive local immune responses, classical IL-6 signaling is obligate for the induction of T cell-mediated autoimmunity.
abstract: IL-6-mediated T cell-driven immune responses are associated with signaling occurring through the membrane-bound cognate receptor α-chain (mIL-6Rα). Once formed, IL-6-mIL-6Rα complexes induce the homodimerization and subsequent phosphorylation of the ubiquitously expressed signal-transducing protein, gp130. This signaling event is defined as classical IL-6 signaling. However, many inflammatory processes assigned to IL-6 may be mediated via binding a naturally occurring soluble IL-6Rα, which forms an agonistic complex (IL-6/soluble IL-6Rα) capable of evoking responses on a wide range of cell types that lack mIL-6Rα (IL-6 trans-signaling). To dissect the differential contribution of the two IL-6 signaling pathways in cell-mediated inflammatory processes, we pharmaceutically targeted each using two murine models of human arthritis. Whereas intra-articular neutralization of trans-signaling attenuated local inflammatory responses, the classical pathway was found to be obligate and sufficient to induce pathogenic T cells and humoral responses, leading to systemic disease. Our data illustrate that mechanisms occurring in the secondary lymphoid organs underlying arthropathies are mediated via the classical pathway of IL-6 signaling, whereas trans-signaling contributes only at the local site, that is, in the affected tissues.
authors.affiliation: NovImmune SA, Geneva, Switzerland.
authors.forename: Rami
authors.initials: R
authors.lastname: Lissilaa
authors.forename: Vanessa
authors.initials: V
authors.lastname: Buatois
authors.forename: Giovanni
authors.initials: G
authors.lastname: Magistrelli
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Jones
authors.forename: Suzanne
authors.initials: S
authors.lastname: Herren
authors.forename: Limin
authors.initials: L
authors.lastname: Shang
authors.forename: Pauline
authors.initials: P
authors.lastname: Malinge
authors.forename: Florence
authors.initials: F
authors.lastname: Guilhot
authors.forename: Laurence
authors.initials: L
authors.lastname: Chatel
authors.forename: Eric
authors.initials: E
authors.lastname: Hatterer
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Marie H
authors.initials: MH
authors.lastname: Kosco-Vilbois
authors.forename: Walter G
authors.initials: WG
authors.lastname: Ferlin
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology*; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D015850:Interleukin-6 / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019947:Receptors, Interleukin-6 / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D019947:Receptors, Interleukin-6