Understanding of biological activities of cytokines and exquisite mechanism to regulate their functions has facilitated the therapeutic concept to restore the disequilibrium between pro-inflammatory cytokines and anti-inflammatory cytokines or cytokine inhibitors in some autoimmune inflammatory diseases such as rheumatoid arthritis (RA) and Crohn's disease. The application of molecular biology techniques to design monoclonal antibodies, soluble receptors, or receptor antagonists as therapeutic biologic agents made it possible to regulate the cytokine signals for the treatment of the diseases refractory to conventional therapies. Japanese researchers have contributed considerably to the establishment of cytokine signal regulation in autoimmune diseases. In this article, Japanese studies of cytokine signal regulation, particularly for Interleukin-6 (IL-6) in autoimmune diseases are reviewed.