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


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.


Aoyama A, Tonsho M, Smith R‐N, et al. (2016) Non‐human primate lung allograft survival is prolonged by il‐6 inhibition and ATG treatment possibly through expansion of peripheral regulatory Tcells [Abstract]. American Transplant Congress.

Baldwin WM 3rd, Samaniego‐Picota M, Kasper EK, et al. (1999) Complement deposition in early cardiac transplant biopsies is associated with ischemic injury and subsequent rejection episodes. Transplantation 68 (6): 894–900.

Bommert K, Bargou RC and Stuhmer T (2006) Signalling and survival pathways in multiple myeloma. European Journal of Cancer 42 (11): 1574–80.

Booth AJ, Garabauskiene S, Wood SC, et al. (2011) IL‐6 promotes cardiac graft rejection mediated by CD4+ cells. Journal of Immunology 187 (11): 5764–71.

Calabrese LH and Rose‐John S (2014) IL‐6 biology: implications for clinical targeting in rheumatic disease. Nature Reviews Rheumatology 10 (12): 720–7.

Campbell IL, Abraham CR, Masliah E, et al. (1993) Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proceedings of the National Academy of Sciences of the United States of America 90 (21): 10061–5.

Casiraghi F, Ruggenenti P, Noris M, et al. (1997) Sequential monitoring of urine‐soluble interleukin 2 receptor and interleukin 6 predicts acute rejection of human renal allografts before clinical or laboratory signs of renal dysfunction. Transplantation 63 (10): 1508–14.

Chandesris MO, Melki I, Natividad A, et al. (2012) Autosomal dominant STAT3 deficiency and hyper‐IgE syndrome: molecular, cellular, and clinical features from a French national survey. Medicine (Baltimore) 91 (4): e1–19.

Chandran S, Leung J, Laszik Z, et al. (2018) IL‐6 inhibition with tocilizumab to promote tregs and control renal graft infl ammation: a prospective randomized controlled trial [abstract]. American Journal of Transplantation 18 (suppl. 4).

Chavele KM, Merry E and Ehrenstein MR (2015) Cutting edge: circulating plasmablasts induce the differentiation of human T follicular helper cells via IL‐6 production. Journal of Immunology 194 (6): 2482–5.

Choi J, Vo A, Kahwaji J, et al. (2015) Long term outcomes of tocilizumab therapy for DSA+ antibody mediated rejection (ABMR) resistant to IVIG + rituxan (I + R) treatment [Abstract]. American Transplant Congress.

Choi J, Aubert O, Vo A, et al. (2017) Assessment of tocilizumab (anti‐interleukin‐6 receptor monoclonal) as a potential treatment for chronic antibody‐mediated rejection and transplant glomerulopathy in HLA‐sensitized renal allograft recipients. American Journal of Transplantation 17 (9): 2381–2389.

Chung BH, Kim KW, Kim BM, et al. (2015) Increase of Th17 cell phenotype in kidney transplant recipients with chronic allograft dysfunction. PLoS ONE 10 (12): e0145258. (2015) Extension Study Of Stage 1 Subjects Of Study A3921009 For The Prevention Of Acute Rejection In Kidney Transplant Patient., (2017a) Clazakizumab for chronic and active antibody mediated rejection post‐kidney transplant., (2017b) A pilot trial of clazakizumab in late ABMR.

Farrar CA, Kupiec‐Weglinski JW and Sacks SH (2013) The innate immune system and transplantation. Cold Spring Harbor Perspectives in Medicine 3 (10): a015479.

Garbers C, Aparicio‐Siegmund S and Rose‐John S (2015) The IL‐6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Current Opinion in Immunology 34: 75–82.

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

He J, Shi J, Xu X, et al. (2012) STAT3 mutations correlated with hyper‐IgE syndrome lead to blockage of IL‐6/STAT3 signalling pathway. Journal of Biosciences 37 (2): 243–57.

Heink S, Yogev N, Garbers C, et al. (2017) Trans‐presentation of IL‐6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nature Immunology 18 (1): 74–85.

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

Jerkeman M and Linden O (2016) Long‐term remission in idiopathic Castleman's disease with tocilizumab followed by consolidation with high‐dose melphalan‐‐two case studies. European Journal of Haematology 96 (5): 541–3.

Jones SA, Scheller J and Rose‐John S (2011) Therapeutic strategies for the clinical blockade of IL‐6/gp130 signaling. The Journal of Clinical Investigation 121 (9): 3375–83.

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.

Jurewicz M, Takakura A, Augello A, et al. (2010) Ischemic injury enhances dendritic cell immunogenicity via TLR4 and NF‐kappa B activation. Journal of Immunology 184 (6): 2939–48.

Kang S, Tanaka T and Kishimoto T (2015) Therapeutic uses of anti‐interleukin‐6 receptor antibody. International Immunology 27 (1): 21–9.

Kikuchi J, Hashizume M, Kaneko Y, et al. (2015) Peripheral blood CD4(+)CD25(+)CD127(low) regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response. Arthritis Research & Therapy 17: 10.

Kishimoto T, Hibi M, Murakami M, et al. (1992) The molecular biology of interleukin 6 and its receptor. Ciba Foundation Symposium 167: 5–16; discussion 16–23.

Leung J, Chandran S, Flavio V, et al. 2018 Immunologic impact of tocilizumab treatment in kidney transplant recipients with allograft inflammation [abstract]. American Journal of Transplantation 18(suppl 4).

Lion J, Taflin C, Cross A, et al. (2016) HLA class II antibody activation of endothelial cells promotes Th17 and disrupts regulatory T lymphocyte expansion. American Journal of Transplantation 16 (5): 1408–20.

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

Longhi MP, Wright K, Lauder SN, et al. (2008) Interleukin‐6 is crucial for recall of influenza‐specific memory CD4 T cells. PLoS Pathogens 4 (2): e1000006.

Mesin L, Di Niro R, Thompson KM, et al. (2011) Long‐lived plasma cells from human small intestine biopsies secrete immunoglobulins for many weeks in vitro. Journal of Immunology 187 (6): 2867–74.

Mulvihill MS, Gulack BC, Ganapathi AM, et al. (2017) The association of donor age and survival is independent of ischemic time following deceased donor lung transplantation. Clinical Transplantation: 31(7).

Regeneron Pharmaceuticals Inc. Press (2017) Regeneron Pharmaceuticals, Inc. Press Release May 2017 [cited 2018 July].

Shapiro‐Shelef M, Lin K, Savitsky D, et al. (2005) Blimp‐1 is required for maintenance of long‐lived plasma cells in the bone marrow. The Journal of Experimental Medicine 202 (11): 1471–6.

Sonkar GK, Singh S, Sonkar SK, et al. (2013) Evaluation of serum interleukin 6 and tumour necrosis factor alpha levels, and their association with various non‐immunological parameters in renal transplant recipients. Singapore Medical Journal 54 (9): 511–5.

Suematsu S, Matsuda T, Aozasa K, et al. (1989) IgG1 plasmacytosis in interleukin 6 transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 86 (19): 7547–51.

Tanaka T, Narazaki M and Kishimoto T (2014) IL‐6 in inflammation, immunity, and disease. Cold Spring Harbor Perspectives in Biology 6 (10): a016295.

Tse GH, Johnston CJ, Kluth D, et al. (2015) Intrarenal B cell cytokines promote transplant fibrosis and tubular atrophy. American Journal of Transplantation 15 (12): 3067–80.

Uehara M, Solhjou Z, Banouni N, et al. (2018) Ischemia augments alloimmune injury through IL‐6‐driven CD4(+) alloreactivity. Scientific Reports 8 (1): 2461.

Van Oers MH, Van der Heyden AA and Aarden LA (1988) Interleukin 6 (IL‐6) in serum and urine of renal transplant recipients. Clinical and Experimental Immunology 71 (2): 314–9.

Vandenbroecke C, Caillat‐Zucman S, Legendre C, et al. (1991) Differential in situ expression of cytokines in renal allograft rejection. Transplantation 51 (3): 602–9.

Winthrop KL (2017) The emerging safety profile of JAK inhibitors in rheumatic disease. Nature Reviews Rheumatology 13 (4): 234–243.

Wood KJ, Bushell A and Hester J (2012) Regulatory immune cells in transplantation. Nature Reviews. Immunology 12 (6): 417–30.

Wu Y, El Shikh M, El Sayed R, et al. (2009) IL‐6 produced by immune complex‐activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation. International Immunology 21 (6): 745–56.

Zhang H, Thomas D, Kowalewska J, et al (2015) Differentially expressed IL‐6Rα and GP130 genes in kidney biopsies (Bxs) suggests different roles of IL‐6 signaling in antibody (ABMR)‐ and cell (CMR)‐mediated rejection [Abstract]. American Transplant Congress.

Zhang H, Huang E, Kahwaji J, et al. (2017) Plasma exosomes from HLA‐sensitized kidney transplant recipients contain mRNA transcripts which predict development of antibody‐mediated rejection. Transplantation 101 (10): 2419–2428.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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. [doi: 10.1002/9780470015902.a0028204]