IL-6 in inflammation, immunity, and disease

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 shown 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 to facilitate the development of more specific therapeutic approaches and analysis of the pathogenesis of specific diseases.

Figure 1.

IL-6 in inflammation, immunity, and disease. IL-6 is a cytokine featuring pleiotropic activity; it induces synthesis of acute phase proteins such as CRP, serum amyloid A, fibrinogen, and hepcidin in hepatocytes, whereas it inhibits production of albumin. IL-6 also plays an important role on acquired immune response by stimulation of antibody production and of effector T-cell development. Moreover, IL-6 can promote differentiation or proliferation of several nonimmune cells. Because of the pleiotropic activity, dysregulated continual production of IL-6 leads to the onset or development of various diseases. Treg, regulatory T cell; RANKL, receptor activator of nuclear factor κB (NF-κB) ligand; VEGF, vascular endothelial growth factor.

Figure 2.

Transcriptional and posttranscriptional regulation of IL-6 gene. The expression and degradation of IL-6 mRNA is regulated transcriptionally and posttranscriptionally by several proteins and microRNAs. Activation of these proteins and microRNAs determines the fate of IL-6 mRNA. NF-IL-6, nuclear factor of IL-6; Tax, transactivator protein; TAT, transactivator of the transcription; HBVX, hepatitis B virus X protein; Ahr, aryl hydrocarbon receptor; GR, glucocorticoid receptor; ER, estrogen receptor; Rb, retinoblastoma; PPARα, peroxisome proliferator–activated receptor α; miR, microRNA; IRAK1, IL-1 receptor–associated kinase 1; STAT3, signal transducer and activator of transcription 3; ORF, open reading frame; TTP, tristetraprolin; BRF1, butyrate response factor 1.

Figure 3.

IL-6 synthesis and regulation of IL-6 mRNA stability by Arid5a. Pathogen-associated molecular patterns are recognized by pathogen-recognition receptors to induce proinflammatory cytokines; in this figure, TLR4 recognizes LPS and induces IL-6 mRNA via activation of the NF-κB signaling pathway. Regnase-1 promotes IL-6 mRNA degradation, whereas Arid5a inhibits destabilizing effects of regnase-1. The balance between Arid5a and regnase-1 is important for the regulation of IL-6 mRNA. MD2, myeloid differentiation protein 2; MyD88, myeloid differentiation primary response 88; IκB, inhibitor of NF-κB.

Figure 4.

IL-6 receptor system and IL-6 blocker, a humanized anti-IL-6 receptor antibody tocilizumab. IL-6 binds to soluble and transmembrane IL-6R and the complex, then induces homodimerization of gp130, leading to activation of the signaling system. A humanized anti-IL-6R antibody, tocilizumab, blocks IL-6-mediated signaling pathway by its inhibition of IL-6 binding to both receptors. JAKs, Janus kinases; SHP-2, SH2-domain containing protein tyrosine phosphatase-2.

Figure 5.

Major discoveries in IL-6-related research and establishment of IL-6 targeting strategy for immune-mediated diseases. Basic research regarding IL-6 clarified the molecular basis of the characteristics of cytokine, redundancy, and pleiotropy, whereas clinical research revealed its pathological significance in disease development. These findings led to concept that IL-6 targeting would constitute a novel therapeutic strategy for immune-mediated diseases and indeed, tocilizumab, a humanized anti-IL-6R antibody became an innovative biologic for the treatment of intractable diseases such as RA, systemic juvenile idiopathic arthritis (sJIA), and Castleman’s disease. It will be expected that this strategy would be widely applicable for other immune-mediated diseases. LNs, lymph nodes; TCZ, tocilizumab; CDR, complementarity determining region.