Interleukin 6 and rheumatoid arthritis

Abstract

Interleukin-6 (IL-6) is a representative cytokine featuring pleiotropic activity and redundancy. A transient synthesis of IL-6 contributes to host defense against infectious agents and tissue injuries by inducing acute phase reactions and immunological and hematopoietic responses. However, uncontrolled persistent production of IL-6 may lead to the development of several immune-mediated diseases. Rheumatoid arthritis (RA) is a chronic disease with joint and systemic inflammation resulting from immunological abnormalities and it has been found that IL-6 plays a key role in the development of this disease. Clinical trials in various parts of the world of tocilizumab, a humanized anti-IL-6 receptor antibody, have proved its efficacy and tolerable safety either as monotherapy or in combination with disease-modifying antirheumatic drugs. As a result, it is currently used as a first-line biologic for the treatment of moderate-to-severe RA in more than 100 countries. Clarification of the mechanism(s) through which tocilizumab exerts its effect on RA and of the reason(s) why IL-6 is continuously produced in RA can be expected to lead to the best use of this agent for RA patients and aid in investigations into the pathogenesis of RA.

Figure 1

IL-6 exerts its pleiotropic activity by activation of gp130 through its binding to transmembrane or soluble IL-6 receptor. IL-6 initiates the IL-6 signaling pathway through binding to transmembrane or soluble IL-6 receptor. The resultant complex then induces homodimerization of gp130, which leads to activation of a signaling system. Transcriptional factors including STAT3 activate various gene expressions, resulting in cell differentiation or proliferation. JAKs: Janus kinases; STAT3: signal transducer and activator of transcription 3; SHP-2: SH2 domain-containing tyrosine phosphatase 2; PI3K: phosphoinositol-3 kinase; Grb2, growth factor receptor-bound protein 2; ERK: extracellular signal-regulated kinase; MAPK: mitogen activated protein kinase; Akt: protein kinase B; TGF-β: transforming growth factor beta; CRP: C-reactive protein; SAA: serum amyloid A; MMPs: matrix metalloproteinases.