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

Lissilaa, Rami, Buatois, Vanessa, Magistrelli, Giovanni, Williams, Anwen Sian ORCID: https://orcid.org/0000-0001-6118-020X, Jones, Gareth Wyn, Herren, Suzanne, Shang, Limin, Malinge, Pauline, Guilhot, Florence, Chatel, Laurence, Hatterer, Eric, Jones, Simon Arnett ORCID: https://orcid.org/0000-0001-7297-9711, Kosco-Vilbois, Marie H. and Ferlin, Walter G. 2010. 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. The Journal of Immunology 185 (9) , pp. 5512-5521. 10.4049/jimmunol.1002015

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Last Modified:	06 Nov 2022 14:34
URI:	https://orca.cardiff.ac.uk/id/eprint/29843

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