“Interleukin 6 Amplifier: A key player in inflammatory diseases

How extensive a view from the top of the mountain is!

Toshio Hirano

Nobel Forum, Karolinska Institute, Stockholm, Sweden

May 12, 2009

Thirty years ago, I found pleural effusion cells in patients with tuberculous pleurisy produce an active factor that induces immunoglobulin production in B cells and started isolating it. In 1986, we succeeded to clone IL-6 and thereafter both its receptor and gp130, a signal transducer. IL-6 was found to be a multifunctional cytokine and its involvement in rheumatoid arthritis (RA) was suggested. We then showed IL-6 induces both STAT3 and SHP2/Gab/MAPK signals. To clarify the in vivo roles of each signal, we made several knock-in mice expressing mutated variants of gp130, and showed F759 mice, which have an amino acid substitution (Y759F) and an enhanced STAT3 activation, developed a RA-like arthritis. F759 arthritis was dependent on CD4+T cells, IL-6 and IL-17 and it was enhanced by the T cell leukemia virus 1 p40-Tax, suggesting STAT3 and NF-κB involvement. The F759 mutation in non-hematopoietic cells was required for the arthritis development, indicating interaction between non-immune tissues and the immune system plays a key role in the disease. We showed the IL-6 amplifier driven by STAT3 and NF-κB was the consequences of this interaction and it played a role in F759 arthritis. This scenario may be a general etiologic process underlying other autoimmune diseases and inflammatory diseases.

See Crafoord Days 2009 and Crafoord Prize Lectures 2009  at

http://www.crafoordprize.se/events/crafoorddays20082009.4.2f692b3510dbfce339680003937.html