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

Rami Lissilaa, Vanessa Buatois, Giovanni Magistrelli, Anwen Sian Williams, Gareth Wyn Jones, Suzanne Herren, Limin Shang, Pauline Malinge, Florence Guilhot, Laurence Chatel, Eric Hatterer, Simon Arnett Jones, Marie H. Kosco-Vilbois, Walter G. Ferlin

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

IL-6?mediated T cell-driven immune responses are associated with signaling occurring through the membrane-bound cognate receptor alpha-chain (mIL-6Ralpha). Once formed, IL-6?mIL-6Ralpha 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-6Ralpha, which forms an agonistic complex (IL-6/soluble IL-6Ralpha) capable of evoking responses on a wide range of cell types that lack mIL-6Ralpha (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.
Original languageUndefined/Unknown
Pages (from-to)5512-5521
Number of pages10
JournalJournal of Immunology
Volume185
Issue number9
Publication statusPublished - 1 Nov 2010

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