Interleukin-6 (IL-6) is a multifunctional cytokine that induces differentiation of B cells to antibody-producing plasma cells; induces activated T cells; acts on hepatocytes to induce acute-phase reactants, including C-reactive protein (CRP) and fibrinogen; and decreases serum albumin level. It has also been shown that IL-6 is responsible for various symptoms, including the appearance of autoantibodies, fatigue, anemia, anorexia, fever, and increases in erythrocyte sedimentation rate and CRP - all of which develop in patients with various chronic autoimmune inflammatory diseases. In addition, blocking the IL-6 signaling pathway with an anti-IL-6 receptor antibody has been reported to improve all these signs and symptoms developed in these patients.

Until recently, it was believed that there were only two types of T helper cells: Th1 and Th2. However, considerable evidence indicates that a new type of cells, called Th17 helper cells, might play an important role in the pathogenesis of autoimmune diseases. Th17 helper cells produce a cytokine called IL-17, which is generally thought to enhance inflammation by recruiting other immune cells to peripheral tissues. There are now many lines of evidence that IL-17 is a pathogenic effecter molecule in autoimmune inflammatory disorders. As reported by Paul R. Mangan of the University of Alabama at Birmingham and his colleagues, transforming growth factor-beta (TGF ß )-deficient mice had reduced numbers of Th17 cells. ¹ Similarly, Estelle Bettelli of the center for neurological diseases at Brigham and Women's Hospital in Boston and her colleagues showed that TGF ß -transgenic mice had increased numbers of Th17 cells and more severe autoimmune diseases. ² These results clearly demonstrated that TGF ß is essential for the induction of Th17 cells. But more important, papers recently published have shown that IL-6 promotes the development of Th17 cells and that anti-IL-6 antibody almost completely inhibited Th17 cell differentiation, even in the presence of TGF ß . ³ Moreover, it is also reported that a cocktail of TGF ß and IL-6 decreased regulatory T cells, although TGF ß itself induces the differentiation of regulatory T cells. ²

These findings suggest that there may be a new dichotomy in helper T-cell differentiation, and IL-6 might be a crucial factor to polarize to increase Th17 cells and to inhibit regulatory T cells, leading to autoimmunity.

Yoshiyuki Ohsugi is the science director for the MRA unit (a humanized anti-human interleukin-6 receptor monoclonal antibody) at Chugai Pharmaceutical Co. in Tokyo, Japan.