FUNCTIONAL DISTINCTION OF 2 REGIONS OF HUMAN INTERLEUKIN-6 IMPORTANT FOR SIGNAL-TRANSDUCTION VIA GP130

被引：12

作者：

DEHON, FD

TENBOEKEL, E

HERRMAN, J

CLEMENT, C

EHLERS, M

TAGA, T

YASUKAWA, K

OHSUGI, Y

KISHIMOTO, T

ROSEJOHN, S

WIJDENES, J

KASTELEIN, R

AARDEN, LA

BRAKENHOFF, JPJ

机构：

[1] NETHERLANDS RED CROSS,BLOOD TRANSFUS SERV,CENT LAB,DEPT AUTOIMMUNE DIS,1066 CX AMSTERDAM,NETHERLANDS

[2] UNIV AMSTERDAM,EXPTL & CLIN IMMUNOL LAB,AMSTERDAM,NETHERLANDS

[3] DNAX RES INST MOLEC & CELLULAR BIOL INC,PALO ALTO,CA 94304

[4] INNOTHERAPIE,BESANCON,FRANCE

[5] RHEIN WESTFAL TH AACHEN,INST BIOCHEM,W-5100 AACHEN,GERMANY

[6] OSAKA UNIV,INST MOLEC & CELLULAR BIOL,OSAKA,JAPAN

[7] TOSOH CORP,BIOTECHNOL RES LAB,KANAGAWA,JAPAN

[8] CHUGAI PHARMACEUT CO LTD,FUJI GOTEMBA RES LABS,SHIZUOKA,JAPAN

[9] OSAKA UNIV,SCH MED,DEPT MED 3,OSAKA,JAPAN

来源：

CYTOKINE | 1995年 / 7卷 / 05期

关键词：

D O I：

10.1006/cyto.1995.0055

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Mutagenesis of a region of human interleukin (IL)-6 which is important for triggering signal transduction via the IL-6 receptor beta-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-1, 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-1 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-6R alpha-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. (C) 1995 Academic Press Limited.

引用

页码：398 / 407

页数：10

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