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*

Department of Clinical Application of Biologics, Osaka University Graduate School of

Medicine, Osaka University, Osaka 565-0871, Japan.
2

Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University

Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
3

Laboratory 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 Castlemans 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 immunemediated 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.

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.

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