Functional distinction of two regions of human interleukin 6 important for signal transduction via gp130

Floris D. de Hon, Edwin ten Boekel, Jean Herrman, Claude Clement, Marc Ehlers, Tetsuya Taga, Kiyoshi Yasukawa, Yoshiyuki Ohsugi, Tadamitsu Kishimoto, Stefan Rose-John, John Wijdenes, Rob Kastelein, Lucien A. Aarden, Just P.J. Brakenhoff

12 Citations (Scopus)

Abstract

Mutagenesis of a region of human interleukin (IL)-6 which is important for triggering signal transduction via the IL-6 receptor β-chain (gp130) has lead to the isolation of a variant of human IL-6 (IL-6.Q160E/T163P), which could antagonize the biological activity of wild type IL-6 on the human EBV transformed B cell line CESS and the human hepatoma cell line HepG2. Surprisingly this antagonistic IL-6 variant had an agonistic effect on the human myeloma cell line XG-l, albeit at a 1000-fold higher concentration than wild type IL-6. This residual activity of the mutant arose from triggering gp130, because it could be inhibited by a gp130 specific mAb. Extensive mutagenesis of residues between Q153 and H165 of human IL-6, a region which is partly homologous in cytokines which also signal via gp130 (oncostatin M, ciliary neurotrophic factor, leukaemia inhibitory factor, IL-11), did result in the isolation of a second antagonist for IL-6 activity on CESS and HepG2 cells. However on XG-l cells this variant was active as well. These results suggest that (an) additional region(s) of the IL-6 molecule might be involved in gp130 triggering. Recently we indeed found that residues Lys42-Ala57 are also important for gp130 triggering. Inhibition experiments with neutralizing IL-6Rα-chain specific mAb show that this region can be functionally separated from the Q153-H165 region. These findings have important implications for the development of receptor antagonists of IL-6 and IL-6 family members.

Original languageEnglish
JournalCytokine
Volume7
Issue number5
Pages (from-to)398-407
Number of pages10
ISSN1043-4666
DOIs
Publication statusPublished - 01.01.1995

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