Interleukin 6: Pathogenic Potential and Therapeutic Approaches in Autoimmunity and Transplant Rejection

Abstract

Interleukin 6 (IL‐6) is a cytokine critical to the function of innate and adaptive immunity. IL‐6 has a diverse acumen of immunologic and physiologic activities including direction of immune cell differentiation and initial responses to invading pathogens and ischemic injury. Dysregulation of IL‐6 transcription is often seen in patients with autoimmune and inflammatory disorders. Emerging information also suggests IL‐6 transcription dysregulation is present in patients with kidney and heart transplant rejection and may account for perpetuation of inflammatory responses in the allograft. IL‐6 directed therapeutics include monoclonal antibodies aimed at IL‐6 and the IL‐6 receptor (IL‐6R) as well as Janus kinase (JAK) inhibitors. IL‐6‐mediated signalling to cell targets is unique and involves classic signalling (IL‐6‐>IL‐6R) cell membrane receptors, trans‐signalling (IL‐6‐>soluble IL‐6R‐>gp130), which can activate any cell and the newly described IL‐6/IL‐6R trans‐presentation where antigen‐presenting cells (APC) express IL‐6/IL‐6R complexes and co‐stimulate T‐cells. Currently, there are new trials in autoimmunity and specifically heart and kidney transplantation to determine efficacy in blocking IL‐6/IL‐6R for amelioration of chronic allograft rejection.

Key Concepts

  • IL‐6 is a multifunctional cytokine, produced by almost every stromal cell and immune cell in the human body.
  • IL‐6 plays an important role in the induction of Tfh cells that are critical for initiation of GC formation and progression of naïve B‐cells to plasma cells and production of high‐affinity antibodies.
  • IL‐6 signalling inhibition is emerging as a therapeutic approach to a number of conditions varying from autoimmune diseases, cancer and organ transplantation.
  • IL‐6 mediates injury to allografts in humans.
  • IL‐6 directed therapeutics may be a consideration for long‐term maintenance therapy to reduce chronic injury to the allografts.

Keywords: interleukin 6; immunology; IL‐6 directed therapy; ischaemia‐reperfusion injury; kidney transplantation

Figure 1. (a) Depicts the essential features of the classic IL‐6/IL‐6R signalling pathway. Here, circulating IL‐6 binds to the nonsignalling IL‐6R. This IL‐6/IL‐6R cassette then activates gp130 on the cell membrane, inducing signal transduction pathways leading to JAK/STAT3 activation and gene transcription. Classic IL‐6/IL‐6R signalling is limited to hepatocytes and some leukocyte subsets. (b) Shows the unique trans‐signalling pathway which expands the activation capacities of sIL‐6R/IL‐6 to nearly every cell in the body. Here, sIL‐6R is generated by alternative gene splicing of IL‐6R mRNA or enzymatic cleavage by a disintegrin and metalloproteinase domain (ADAM10 & ADAM17) from cell membranes. Circulating sIL‐6R binds to IL‐6 forming sIL‐6R/IL‐6 or (‘super IL‐6’) capable of binding to gp130 expressing cells and activating the JAK/STAT3 pathway as previously described. Sgp130 is also present in serum and can act to modify sIL‐6R/IL‐6 trans‐signalling by competitive binding. (c) Describes a recently discovered signalling pathway (trans‐presentation) and third mode of IL‐6/IL‐6R signalling in the immune system. This system is currently confirmed only in mice. Briefly, this mode of IL‐6/IL‐6R signalling occurs in the context of antigen presentation by dendritic cells (DCs) to naïve CD4+ T‐cells. Here, IL‐6 and IL‐6R are expressed in the cytoplasm of DCs which combine and traverse the cell membrane to lock into and activate gp130 molecules on CD4+ T‐cells. This results in phosphorylation and signal transduction by JAK/STAT3 pathway. This co‐stimulatory signal results in the activation of pathogenic inflammatory CD4+ T‐cells. Activation of these naïve CD4+ T‐cells leads to activation of Th17 cells and induction of inflammation, autoimmunity and allograft rejection. IL‐6 production also inhibits regulatory (Treg) cells further enhancing inflammatory injury. (d) Shows the impact of anti‐IL‐6R and anti‐IL‐6 antibodies on inflammatory CD4+ T‐cell induction by IL‐6/IL‐6R trans‐presentation. Briefly, anti‐IL‐6R (but not anti‐IL‐6) can inhibit trans‐presentation. This results in muted CD4+ T‐cell activation and deviation of the inflammatory immune response towards a regulatory and tolerogenic type of response (Treg). After T‐cell activation, anti‐IL‐6 likely inhibits Th17 cells and also contributes to deviation of the immune response towards Tregs.
Figure 2. (a) Shows how IL‐6 drives humoral immune responses. IL‐6 production by APCs is a powerful stimulus for IL‐21 production by naïve T‐cells. This results in maturation of naïve T‐cells toward the Tfh phenotype expressing CXCR5, IL‐21 and the transcription factor Bcl‐6. Naïve B‐cells migrate to the germinal centres in response to CXCR5+ Tfh cells. This activates B‐cell maturation to memory B‐cells and IL‐6 producing plasmablast that further adjuvates germinal centre formation and progression to antibody‐producing plasma cells. The plasma cells have the highest density of IL‐6R compared to other B‐cell subsets, suggesting the importance of IL‐6 in driving pathogenic antibodies and tissue injury. (b) Shows the impact of anti‐IL‐6/IL‐6R therapy on reducing Tfh activation and subsequent plasmablast and plasma cell development with reductions in pathogenic antibody production and tissue injury.
Figure 3. (a) Shows the impact of IL‐6 on shaping T‐cell immune responses. Here, cytokine exposure patterns of naïve T‐cells direct T‐cell effector functions and development. IL‐6 is a critical element for inflammatory T‐cell development. IL‐6 regulates proliferation and function of Th1 and Th2 T‐cells. IL‐6 is a potent inhibitor of Treg development by inhibiting the transcription factor FoxP3, thus removing any inhibitory effects of IL‐6 induction of Th17 and Tfh cells. IL‐6 initiates STAT3 activation pathways and is critical for T‐cell infiltration controlled by IL‐6 induced chemokine receptors. The net impact of unfettered IL‐6 expression is polyclonal IgG production, autoimmunity, alloimmunity, lymphadenopathy and capillary leak syndrome. (b) Shows the impact of anti‐IL‐6/IL‐6R therapy on IL‐6 driven T‐cell effector functions. First, blocking IL‐6/IL‐6R interactions allows Treg cells to be activated and counteract Th17 and Tfh cells induced by IL‐6. The net effect is restoration of a noninflammatory phenotype including increased Tregs and decreased Tfh/Th17 cells. These functions should have an important impact in treating autoimmune diseases and transplant rejection.
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Further Reading

Garbers C, Heink S, Korn T and Rose‐John S (2018) Interleukin‐6: designing specific therapeutics for a complex cytokine. Nature Reviews. Drug Discovery 17 (6): 395–412.

Hunter CA and Jones SA (2015) IL‐6 as a keystone cytokine in health and disease. Nature Immunology 16 (5): 448–57.

Jordan SC, Choi J, Kim I, et al. (2017) Interleukin‐6, a cytokine critical to mediation of inflammation, autoimmunity and allograft rejection: therapeutic implications of IL‐6 receptor blockade. Transplantation 101 (1): 32–44.

Liu X, Jones GW, Choy EH and Jones SA (2016) The biology behind interleukin‐6 targeted interventions. Current Opinion in Rheumatology 28 (2): 152–60.

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Jordan, Stanley C, Ammerman, Noriko, Choi, Jua, Huang, Edmund, Toyoda, Mieko, Kim, Irene, Wu, Gordon, and Vo, Ashley(Dec 2018) Interleukin 6: Pathogenic Potential and Therapeutic Approaches in Autoimmunity and Transplant Rejection. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028204]