Interleukin (IL-6) Immunotherapy

Abstract

Interleukin 6 (IL-6) is a prototypical cytokine for maintaining homeostasis. When homeostasis is disrupted by infections or tissue injuries, IL-6 is produced immediately and contributes to host defense against such emergent stress through activation of acute-phase and immune responses. However, dysregulated excessive and persistent synthesis of IL-6 has a pathological effect on, respectively, acute systemic inflammatory response syndrome and chronic immune-mediated diseases. The IL-6 inhibitor, tocilizumab, a humanized anti-IL-6 receptor antibody, is currently being used for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, and Castleman disease. Lines of recent evidence strongly suggest IL-6 blockade can provide broader therapeutic strategy for various diseases included in acute systemic and chronic inflammatory diseases.

Figure 1.

Pleiotropic effect of interleukin 6 (IL-6) (a cytokine featuring pleiotropic activity). It induces synthesis of acute phase proteins in liver such as C-reactive protein (CRP), complement C3, fibrinogen, thrombopoietin, serum amyloid A, and hepcidin, whereas it inhibits production of albumin. IL-6 also plays an important role in acquired immune responses by stimulating antibody production and inducing the differentiation of naïve CD4⁺ T cells into effector T cells. IL-6 activates vascular endothelial cells to produce IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule (ICAM)-1, and C5a receptors, and induces vascular endothelial cadherin disassembly. In addition, IL-6 can promote differentiation or proliferation of several nonimmune cells. Because of its pleiotropic activity, dysregulated persistent or excessive production of IL-6 leads to the onset or development of various diseases. Excessive production of IL-6 is pathologically involved in the swollen lymph nodes of Castleman disease, whereas excessive IL-6 in synovial fluid stimulates fibroblast-like synoviocytes to produce vascular endothelial growth factor (VEGF) and receptor activator of nuclear factor of κB (NF-κB) ligand (RANKL), which enhance angiogenesis and osteoporosis in patients with rheumatoid arthritis. IL-6 supports the survival of plasmablasts, which produce anti-aquaporin 4 antibodies in patients with neuromyelitis optica. Treg, Regulatory T cell.

Figure 2.

Interleukin 6 (IL-6) receptor-mediated signaling pathway and an IL-6 inhibitor, the humanized anti-IL-6 receptor antibody tocilizumab. IL-6 binds to soluble and transmembrane IL-6R and the resultant complex induces homodimerization of gp130, leading to activation of Janus kinase (JAK)1, JAK2, and tyrosine kinase 2 (TYK2). JAKs, in turn, phosphorylate cytoplasmic tyrosine-based motifs of gp130, followed by attracting Src homology 2 (SH2)-containing molecules SH2 domain-containing protein-tyrosine phosphatase 2 (SHP2) to YXXV, signal transducers and activators of transcription (STAT)3 to YXXQ, or STAT1 to YXPQ (Y, tyrosine; V, valine; Q, glutamine; P, proline; X, any amino acid), which results in a downstream signal. Of the negative feedback molecules in cytoplasm, negative feedback molecules, suppressor of cytokine signaling (SOCS)1 binds to and inhibits JAK, whereas SOCS3 binds to gp130 and inhibits STAT3 activation. A humanized anti-IL-6 receptor (IL-6R) antibody, tocilizumab, blocks the IL-6-mediated signaling pathway by inhibiting IL-6 binding to both the soluble and transmembrane form of IL-6Rs. IL-6 can also bind to CD5 with low affinity, which leads to STAT3 activation. MAPKs, Mitogen-activated protein kinases.

Figure 3.

Arid5a stabilizes interleukin 6 (IL-6) and Stat3 messenger RNAs (mRNAs). Toll-like receptor (TLR)4 recognizes lipopolysaccharide (LPS) and induces IL-6 mRNA via activation of the signaling pathway of nuclear factor of κB (NF-κB). Regnase-1 promotes IL-6 mRNA degradation in ribosomes and the endoplasmic reticulum, whereas Arid5a inhibits the destabilizing effect of Regnase-1. Roquin, which requires deadenylase for its function, degrades inactive mRNA in stress granules and processing bodies. In naïve CD4⁺ T cells, IL-6 activates signal transducers and activators of transcription (STAT)3 and induces transcription of IL-6-target genes, including Arid5a, which protects STAT3 mRNA from the degrading effect of Regnase-1. The regulation of IL-6 and STAT3 mRNAs by Arid5a is important for the IL-6 production and strength of the IL-6R-mediated signaling. MyD88, Myeloid differentiation primary response 88; IκB, inhibitor of NF-κB; UTR, untranslated region.

Figure 4.

Interleukin 6 (IL-6) blockade immunotherapy for various diseases. Currently, tocilizumab is approved for the treatment of rheumatoid arthritis, systemic and polyarticular juvenile idiopathic arthritis, and Castleman diseases. It is expected that IL-6 blockade immunotherapy will constitute a novel therapeutic strategy for a wide range of diseases. In particular, the most promising candidate diseases are systemic sclerosis, neuromyelitis, large vessel vasculitis, polymyalgia rheumatica, and cytokine release syndrome (CRS), and ongoing clinical trials are in progress. RS3PE, Remitting seronegative symmetrical synovitis with pitting edema; B-CLL, B-cell chronic lymphocytic leukemia; AML, acute myelogenous leukemia; HIV, human immunodeficiency virus.