IL-6: a cytokine at the crossroads of autoimmunity

Abstract

IL-6 is implicated in the development and progression of autoimmune diseases in part by influencing CD4 T cell lineage and regulation. Elevated IL-6 levels drive inflammation in a wide range of autoimmune diseases, some of which are also characterized by enhanced T cell responses to IL-6. Notably, the impact of IL-6 on inflammation is contextual in nature and dependent on the cell type, cytokine milieu and tissue. Targeting the IL-6/IL-6R axis in humans has been shown to successfully ameliorate a subset of autoimmune conditions. In this review, we discuss recent studies investigating how IL-6 regulates the CD4 T cell response in the context of autoimmune disease and highlight how blocking different aspects of the IL-6 pathway is advantageous in the treatment of disease.

Figure 1.. IL-6 is a proinflammatory modulator of T cells.

IL-6 contributes to autoimmunity by promoting Tfh, Th17, and Teff lineage and function and by inhibiting the suppressive capacity and induction of Tregs. In the presence of IL-21, IL-6 promotes commitment to the Tfh lineage, which is capable of stimulating B cell proliferation and class switching. In addition to bolstering Teff resistance to suppression by Tregs, IL-6 also promotes the conversion of Tregs to Th17 and may reduce Treg suppressive capacity. Lastly, in the presence of TGF-β, IL-6 enhances commitment and function of Th17 cells, a well-established pathogenic cell type in autoimmunity.

Figure 2.. Signaling modes, JAK/STAT cascade and therapeutic targets.

IL-6 signals via three mechanisms: classic signaling mediated by the membrane bound IL-6 receptor (mbIL-6R), trans-signaling mediated by the soluble IL-6 receptor (sIL-6R) and cluster signaling in dendritic cells (DCs). In classic signaling, IL-6 binds the mbIL-6R leading to recruitment of gp130, which then activates JAK1 and JAK2, leading to phosphorylation of the transcription factors, STAT1 and STAT3. Activated STAT3 induces a negative-feedback molecule, suppressor of cytokine signaling (SOCS), SOCS1 and SOCS3. In trans-signaling, IL-6 binds extracellular sIL-6R before complexing with gp130 and initiating the JAK/STAT cascade. Trans-signaling is inhibited by extracellular sgp130, which can complex with sIL-6R and prevent it from binding to the membrane-bound gp130. Classic signaling and trans-signaling may be augmented by ADAM17, which cleaves mbIL-6R to generate sIL-6R. In cluster signaling, IL-6 is complexed with IL-6R within intracellular compartments in DCs before being transported to the membrane to activate gp130 in target cells. Current IL-6 targeting therapies inhibit either IL-6, the IL-6R, or JAK. IL-6 inhibitors include siltuximab, sirukumab, clazakizumab, and olokizumab. Siltuximab is approved for the treatment of Castleman’s disease. Il-6R blocking drugs tocilizumab and sarilumab are both approved for the treatment of RA. Tofacitinib, a JAK inhibitor, is approved for the treatment of RA and has a demonstrated therapeutic effect in ulcerative colitis, alopecia areata, and psoriasis. *indicates FDA approval for an autoimmune disease