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.
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.
Lissilaa
Rami
R
NovImmune SA, Geneva, Switzerland.
Buatois
Vanessa
V
Magistrelli
Giovanni
G
Williams
Anwen S
AS
Jones
Gareth W
GW
Herren
Suzanne
S
Shang
Limin
L
Malinge
Pauline
P
Guilhot
Florence
F
Chatel
Laurence
L
Hatterer
Eric
E
Jones
Simon A
SA
Kosco-Vilbois
Marie H
MH
Ferlin
Walter G
WG
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
D016207:Cytokines; D015850:Interleukin-6; D019947:Receptors, Interleukin-6