New developments in IL-6 dependent biology and therapy: where do we stand and what are the options?
Interleukin-6 (IL-6) is a four-helical protein which, on target cells, binds to a specific IL-6-receptor and two molecules of the promiscuous signal transducing protein gp130. Structure-function analysis defined three molecular contact sites between IL-6 and its receptor subunits. Using this information, competitive antagonistic proteins as well as hyperagonistic proteins were developed. Possible therapeutic applications of IL-6 antagonists are in IL-6 dependent haematological disorders (Castleman's disease, POEMS syndrome, multiple myeloma) and bone diseases (Paget's disease, osteoporosis). Designer IL-6 antagonists could suppress inflammatory activity in rheumatic and autoimmune diseases and could prevent secondary amyloidosis. IL-6 antagonists could also prove advantageous in myocardial infarction and unstable angina pectoris. IL-6 antagonists might slow down development of (mesangioproliferative) glomerulonephritis. On the other hand, hyperagonistic variants of IL-6 have a potential in ex vivo expansion of bone marrow stem cells and as thrombopoietic agents. They might also be developed into drugs to support liver regeneration in vivo and to treat stress-induced cardiac insufficiency.
Medizinische Klinik, Abteilung Pathophysiology Johannes Gutenberg Universität Mainz, Obere Zahlbacher Str. 63, D-55101 Mainz, Germany.
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Kallen
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Galle
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Rose-John