Cold Spring Harbor Perspectives in Biology. 2014 Sep 4;6(10):a016295.

IL-6 in inflammation, immunity, and disease.

Toshio Tanaka1, Masashi Narazaki2, Tadamitsu Kishimoto3*

 

1Department of Clinical Application of Biologics, Osaka University Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.

2Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.

3Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.

*Correspondence: kishimoto@ifrec.osaka-u.ac.jp

 

Abstract

Interleukin 6 (IL-6), promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis and immune reactions. Although its expression is strictly controlled by transcriptional and posttranscriptional mechanisms, dysregulated continual synthesis of IL-6 plays a pathological effect on chronic inflammation and autoimmunity. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody was developed. Various clinical trials have since demonstrated the exceptional efficacy of tocilizumab, which resulted in its approval for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Moreover, tocilizumab is expected to be effective for other intractable immune-mediated diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated in order to facilitate the development of more specific therapeutic approaches and analysis of the pathogenesis of specific diseases.

PMID: 25190079

 

Supplementary

IL-6 is a prototypical cytokine featuring a pleiotropic activity by acting on immune and nonimmune cells (1). IL-6 induces synthesis of acute phase proteins such as C-reactive protein (CRP), serum amyloid A, fibrinogen, and hepcidin in hepatocytes. IL-6 also regulates acquired immune response by stimulation of antibody production and of CD4+ effector T-cell development. In addition, IL-6 can promote megakaryocyte maturation and differentiation and proliferation of various nonimmune cells (Figure 1) (2). When infections or tissue injuries occur, IL-6 is promptly produced by macrophages or monocytes by recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPS), and activates acute phase responses, hematopoiesis, and immune reactions. Once such a stress is removed from the host, the IL-6 synthesis ceases and serum CRP level returns to be normalized.

So, IL-6 expression is strictly regulated, but dysregulated continual or exaggerated production of IL-6 plays a pathological effect on various chronic diseases or severe acute inflammatory conditions, respectively (3). IL-6 can be synthesized by immune cells as well as mesenchymal cells, endothelial cells, fibroblasts, and other cells. In Castleman’s disease germinal center B cells in the involved lymph node(s) spontaneously produce IL-6, which is shown to be responsible for clinical symptoms and signs and inflammatory laboratory findings such as hypergammaglobulinemia, positivity of antinuclear factor, and anemia of chronic disorder. Chimeric antigen receptor-modified T cell therapy is often complicated with “cytokine release syndrome”, in which IL-6 or other cytokines is excessively produced by artificially activated T cells (4).

Thus, IL-6 blockade was expected to be a novel therapeutic strategy for several immune-mediated diseases, and indeed many clinical trials demonstrated the exceptional efficacy of a humanized anti-IL-6 receptor monoclonal antibody, tocilizumab. This biologic is now worldwidely used for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Moreover, various case reports, series, and clinical trials suggest that it will be widely applicable for the treatment of acute and chronic intractable diseases (1-4).

The expression and degradation of IL-6 mRNA is controlled by transcriptional and posttranscriptional mechanisms, in which several transcriptional factors, microRNAs, and RNA-binding proteins are involved. For instance, Regnase-1 plays a role in the degradation of IL-6 mRNA (5), whereas Arid5a counteracts the destabilizing function of Regnase-1 on IL-6 mRNA (6). Therefore, determination of the cell source of IL-6 production and clarification of the mechanism(s) through which IL-6 is produced continuously or excessively will facilitate the identification of more specific target molecule and investigations into the pathogenesis of specific diseases.

 

TT Fig1

Figure 1. IL-6 exerts a pleiotropic activity.

When infections occur, pathogen-associated molecular patterns (PAMPs) interact with pathogen-recognition receptors such as Toll-like receptor (TLR) and stimulate IL-6 production. Produced IL-6 binds to transmembrane or soluble IL-6 receptor (IL-6R), induces homodimerization of gp130, and triggers a downstream signal cascade. Then, IL-6 exerts a pleiotropic activity and contributes to host defense. However, if IL-6 is produced either persistently or excessively, it plays a pathological effect on various diseases. Tocilizumab, a humanized anti-IL-6R monoclonal antibody, inhibits IL-6 binding to both types of IL-6R and is now recognized as the first-in-class biologic for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis.

NF-kB, nuclear factor of kappa beta; JAK, Janus kinase; STAT3, signal transducers and activation of transcription 3; CRP, C-reactive protein; AA, amyloid A; Treg, regulatory T cells; RANKL, receptor activator of NF-kB ligand; VEGF, vascular endothelial growth factor.

 

References

  1. Tanaka T, Narazaki M, Kishimoto T. 2012. Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 52:199-219.
  2. Tanaka T, Narazaki M, Kishimoto T. 2014. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol Sep 4;6(10):a016295.
  3. Kang S, Tanaka T, Kishimoto T. 2015. Therapeutic uses of anti-interleukin-6 receptor antibody. Int Immunol 27(1):21-9.
  4. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. 2014. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507-17.
  5. Matsushita K, Takeuchi O, Standley DM, Kumagai Y, Kawagoe T, Miyake T, Satoh T, Kato H, Tsujimura T, Nakamura H, Akira S. 2009. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458(7242):1185-90.
  6. Masuda K, Ripley B, Nishimura R, Mino T, Takeuchi O, Shioi G, Kiyonari H, Kishimoto T. 2013. Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo. Proc Natl Acad Sci USA 110(23):9409-14.

 

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann