Influence of interleukin-6 (IL-6) dimerization on formation of the high affinity hexameric IL-6 receptor complex
Details
Publication Year 1996-08-16, Volume 271, Issue #33, Page 20138-20144
Journal Title
JOURNAL OF BIOLOGICAL CHEMISTRY
Publication Type
Journal Article
Abstract
The high affinity interleukin-6 (IL-6) signaling complex consists of IL-6 and two membrane-associated receptor components: a low affinity but specific IL-6 receptor and the affinity converter/signal transducing protein gp130. Monomeric (IL-6(M)) and dimeric (IL-6(D)) forms of Escherichia coli-derived human IL-6 and the extracellular (''soluble'') portions of the IL-6 receptor (sIL-6R) and gp130 have been purified in order to investigate the effect of IL-6 dimerization on binding to the receptor complex. Although IL-6(D) has a higher binding affinity for immobilized sIL-6R, as determined by biosensor analysis employing surface plasmon resonance detection, IL-6(M) is more potent than IL-6(D) in a STAT3 phosphorylation assay. The difference in potency is significantly less pronounced when measured in the murine 7TD1 hybridoma growth factor assay and the human hepatoma HepG2 bioassay due to time-dependent dissociation of 37 degrees C of IL-6 dimers into active monomers. The increased binding affinity of IL-6(D) appears to be due to its ability to cross-link two sIL-6R molecules on the biosensor surface. Studies of the IL-6 ternary complex formation demonstrated that the reduced biological potency of IL-6(D) resulted from a decreased ability of the IL-6(D) .(sIL-6R)(2) complex to couple with the soluble portion of gp130. These data imply that the IL-6-induced dimerization of sIL-6R is not the driving force in promoting formation of the hexameric (IL-6 . IL-6R . gp130)(2) complex. A model is presented whereby the trimeric complex of IL-6R, pg130, and IL-6(M) forms before the functional hexamer. Due to its increased affinity for the IL-6R but its decreased ability to couple with gp130, we suggest that a stable IL-6 dimer may be an efficient IL-6 antagonist.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords
SURFACE-PLASMON RESONANCE; SIGNAL TRANSDUCER; MOLECULAR-CLONING; BINDING CONSTANTS; TYROSINE KINASE; 2 DISTINCT; GP130; ASSOCIATION; ACTIVATION; EXPRESSION
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Creation Date: 1996-08-16 12:00:00
Last Modified: 0001-01-01 12:00:00
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