About the Cover
Cytokines are soluble mediators with redundant and pleiotropic activity that aid cell-to-cell communication. IL-6 is a prototypical cytokine, and it contributes to acute-phase host immune response; its synthesis is induced promptly upon tissue damage or inflammation and ceases when homeostasis is restored. The synthesis of IL-6 is tightly regulated transcriptionally and post-transcriptionally, and its dysregulation has been implicated in the development of autoimmune and chronic inflammatory diseases, including cancer. Stability of the IL-6 mRNA is controlled by the binding of microRNAs and RNA-binding proteins to the AU-rich elements at the 3′ untranslated region (UTR). The cover image depicts the regulation of IL-6 synthesis during a pathogenic infection. Bacterial lipopolysaccharide (LPS) binds to the cell-surface Toll-like receptor 4 (TLR4), which activates the synthesis of various proteins, including IL-6, Arid5A, and Regnase-1. Nuclease Regnase-1 binds the 3'UTR of the IL-6 mRNA and accelerates its degradation, while the binding of Arid5a counteracts the destabilizing effect of Regnase-1 on IL-6 mRNA specifically. Therefore, the balance between Arid5a and Regnase-1 plays an important role in IL-6 mRNA stability. When Arid5a dominates the balance of Arid5a and Regnase-1, constitutive overproduction of IL-6 occurs through the stimulation of IL-6R. This positive feedback regulation results in the abnormal production of IL-6 and IL-6–dependent autoimmunity and tumorigenesis. For details, see the Masters of Immunology primer by Tanake and Kishimoto on page 288 of this issue.

About the Master
Tadamitsu Kishimoto, MD, PhD, is an endowed chair professor at the Immunology Research Center of the Osaka University Graduate School of Frontier Biosciences. He is currently Japan's leading scientist in the life sciences, specifically in immunology. Dr. Kishimoto has made fundamental contributions to our understanding of cytokine functions through a comprehensive and elegant series of studies on interleukin (IL)-6, its transcription regulatory factors, its receptor and signal-transduction system, and their utilization by the IL-6 family of cytokines. He has developed humanized monoclonal antibodies to the IL-6 receptor and treatments for immune disorders, including Castleman disease, rheumatoid arthritis, and juvenile idiopathic arthritis.
Dr. Kishimoto was born in Osaka, Japan, in 1939 and was named an honorary citizen of Tondabayashi City in the Osaka Prefecture in 1992. He received an MD (1964) and a PhD in medicine (1969) from Osaka University. During this period, inspired by Dr. Yuichi Yamamura's work on immunology and medicine, Dr. Kishimoto purified and characterized the structure of human IgM from a patient with Waldenstrom macroglobulinemia. He was a research fellow in Dr. Kimishige Ishizaka's laboratory at the Johns Hopkins University, where he studied the regulation of antibody response in an in vitro rabbit lymphocyte system and demonstrated the presence of soluble factors in primed rabbit lymphocytes that enhance antibody production. He showed that the activity inducing the different classes of antibodies is distinct. Dr. Kishimoto returned to his alma mater as a professor and chair of the Department of Medicine, where he discovered and cloned the genes encoding IL-6 and its receptor and delineated the signaling pathway used by the IL-6 family of cytokines. He became the dean of faculty of Osaka University Medical School in 1995. Dr. Kishimoto was the president of Osaka University from 1997 to 2003 and a cabinet member of the Council for Science and Technology Policy Office from 2004 to 2006.
Dr. Kishimoto has received numerous awards, which include the Imperial Prize of the Japan Academy, the Sandoz Prize for Immunology from the International Union of Immunological Society, the Avery-Landsteiner Prize from the German Immunology Society, the Robert Koch Gold Medal, the Crafoord Award from the Royal Swedish Academy of Sciences, and the Japan Prize. He was elected as a Foreign Associate member of both the Institute of Medicine and the U.S. National Academy of Sciences. He is also a member of the Japan Academy and the Deutsche Akademie der Naturforscher Leopoldina and an honorary member of the American Association of Immunologists and the American Society of Hematology. In 1998, Dr. Kishimoto was awarded the Order of Culture from the Emperor of Japan.