The Two-Faced Cytokine IL-6 in Host Defense and Diseases

Abstract

Interleukein-6 (IL-6), is produced locally from infectious or injured lesions and is delivered to the whole body via the blood stream, promptly activating the host defense system to perform diverse functions. However, excessive or sustained production of IL-6 is involved in various diseases. In diseases, the IL-6 inhibitory strategy begins with the development of the anti-IL-6 receptor antibody, tocilizumab (TCZ). This antibody has shown remarkable effects on Castleman disease, rheumatoid arthritis and juvenile idiopathic arthritis. In 2017, TCZ was proven to work effectively against giant cell arteritis, Takayasu arteritis and cytokine releasing syndrome, initiating a new era for the treatment of these diseases. In this study, the defensive functions of IL-6 and various pathological conditions are compared. Further, the diseases of which TCZ has been approved for treatment are summarized, the updated results of increasing off-label use of TCZ for various diseases are reviewed and the conditions for which IL-6 inhibition might have a beneficial role are discussed. Given the involvement of IL-6 in many pathologies, the diseases that can be improved by IL-6 inhibition will expand. However, the important role of IL-6 in host defense should always be kept in mind in clinical practice.

Keywords: IL-6 receptor; cytokine; host defense; inflammation; interleukin-6 (IL-6); pathology; tocilizumab.

Figure 1

Transcriptional and post-transcriptional regulation of interleukein-6 (IL-6) mRNA. Bacterial and fungal components and the molecules derived from tissue injury activate cell surface or intracellular Toll-like receptors (TLRs). Nuclear factor-kappa B (NF-κB) is a main transcriptional factor to induce transcription of IL-6 mRNA. AT-rich interactive domain-containing protein 5a (Arid5a) translocates into the nucleus via an importin-α/β1 pathway and binds to the 3′UTR of IL-6 mRNA. Then, Arid5a exports IL-6 mRNA to the cytoplasm via the chromosomal region maintenance 1 (CRM1) pathway by binding to up-frameshift protein 1 (UPF1) and protects IL-6 mRNA from degradation by Regulatory RNase-1 (Regnase-1). Regnase-1 degrades transcriptionally active IL-6 mRNA by binding to the IL-6 3′UTR in the cytoplasm, endoplasmic reticulum and ribosomes. Another RNA-binding protein Roquin recognizes mRNAs overlapping with Regnase-1. However, Roquin degrades inactive mRNA by recruiting deadenylase in stress granules and processing bodies. The balance between the degradation of IL-6 mRNA by Regnase-1 and the protection of IL-6 mRNA by Arid5a controls the quantity of IL-6 production.

Figure 2

IL-6 signal transduction and modes of the IL-6 receptor system. IL-6 binds to the IL-6 receptor (IL-6R). The IL-6/IL-6R complex is associated with gp130, resulting in a hexamer structure. Homodimerization of gp130 activates Janus kinase (JAK) and subsequently activates Signal transducer and activator of transcription 3 (STAT3), STAT1 and SH2 domain-containing protein-tyrosine phosphatase 2 (SHP2). STAT3 and STAT1 move into the nucleus and SHP-2 activates the Ras-MAP kinase pathway. STAT3 induces the negative feedback molecules suppressor of cytokine signaling 1 (SOCS1) and SOCS3. SOCS1 inhibits JAKs. SOCS3 inhibits the SHP2 pathway. STAT3 also induces Arid5a, which stabilizes Stat3 mRNA by binding to the Stat3 3′UTR. IL-6 signaling via membrane IL-6R or soluble IL-6R is called classic signaling or trans-signaling, respectively. When an IL-6R-expressing cell and a gp130-expressing cell are in close proximity, IL-6 is presented by between cells, a process called trans-presentation. IL-6 also activates gp130 in the endosomal compartment, endoplasmic reticulum (ER), or Golgi body through intracellular signaling. The red arrow indicates signal transduction.

Figure 3

Defense reaction and pathological role of IL-6 in each organ. The defensive role of IL-6 in each organ is closely related to the pathological condition present. In the liver, IL-6 induces acute phase proteins, liver regeneration and CD8 T cell activation. Continuous elevation of IL-6 results in secondary amyloidosis, cardiovascular disease and hepatocellular carcinoma. In hematopoiesis, IL-6 induces leukocytosis by mobilization of neutrophils from the marginal pool into the circulation pool. IL-6 or IL-6-induced thrombopoietin induces thrombocytosis. IL-6-induced hepcidin reduces serum iron levels, leading to anemia. IL-6 plays a crucial role in neutrophil to mononuclear cell transition, B and T cell differentiation. High levels of IL-6 bound with sIL-6R induce vascular permeability in vessels and angiogenesis in chronic inflammatory sites. In bone homeostasis, IL-6 induces osteoclastogenesis. IL-6 activates the coagulation system for hemostasis, together with increases in fibrinogen and platelets, leading to an increased risk for the development of cardiovascular diseases. IL-6 also plays a protective role in intestinal epithelial cells. Accumulating evidence shows the association of IL-6 with a depressed mood. MCP-1: monocyte chemotactic protein 1, ICAM-1: intercellular adhesion molecule-1, RANKL: receptor activator of nuclear factor κB ligand.

Figure 4

IL-6 inhibition therapy for various diseases. Currently, tocilizumab is approved for the treatment of Castleman disease, rheumatoid arthritis, systemic and polyarticular juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis and cytokine releasing syndrome. IL-6 inhibition therapy is expected to constitute a novel therapeutic strategy for a wide range of diseases. Many case reports have also indicated that IL-6 inhibition is an effective treatment for various diseases. Clinical trials for some of them are ongoing.