Targeting interleukin-6: all the way to treat autoimmune and inflammatory diseases

Abstract

Interleukin (IL)-6, a cytokine featuring redundancy and pleiotropic activity, contributes to host defense against acute environmental stress, while dysregulated persistent IL-6 production has been demonstrated to play a pathological role in various autoimmune and chronic inflammatory diseases. Targeting IL-6 is thus a rational approach to the treatment of these diseases. Indeed, clinical trials of tocilizumab, a humanized anti-IL-6 receptor antibody have verified its efficacy and tolerable safety for patients with rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis, resulting in approval of this innovative biologic for treatment of these diseases. Moreover, a considerable number of case reports and pilot studies of off-label use of tocilizumab point to the beneficial effects of tocilizumab for a variety of other phenotypically different autoimmune and chronic inflammatory diseases. Elucidation of the source of IL-6 and of mechanisms through which IL-6 production is dysregulated can thus be expected to lead to clarification of the pathogenesis of various diseases.

Keywords: a humanized anti-interleukin-6 receptor antibody; autoimmune; inflammation.; interleukin-6; tocilizumab.

Figure 1

IL-6 has a pleiotropic effect but its dysregulated persistent production causes the onset and development of various autoimmune and chronic inflammatory diseases. IL-6 is originally found as a B cell stimulatory factor-2, which induces activated B cells into antibody production. IL-6, combined with TGF-β, preferentially induces the differentiation of naïve CD4 positive T cells into Th17 cells whereas IL-6 inhibits TGF-β induced regulatory T cell (Treg) development. As a consequence, Th17/Treg imbalance may cause the onset and progression of autoimmune and chronic inflammatory diseases. IL-6 induces production of acute-phase proteins such as CRP, fibrinogen, serum amyloid A, and hepcidin, whereas it reduces synthesis of albumin in hepatocytes. High persistent levels of serum amyloid A and hepcidin lead to amyloid A amyloidosis and anemia of inflammation, respectively. In bone marrow, IL-6 induces maturation of megakaryocytes into platelets and activation of hematopoietic stem cells. In addition, IL-6 promotes the differentiation of osteoclasts and angiogenesis, the proliferation of keratinocytes and mesangial cells, and the growth of myeloma and plasmacytoma cells. Treg: regulatory T cells; CRP: C-reactive protein; VEGF: vascular endothelial growth factor; RANKL: receptor activator of NF-kappaB ligand.