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*
Institut für Biochemie, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany; and
Diaclone, Besançon, France
Soluble receptors for several cytokines have been detected
in body fluids and are believed to modulate the cytokine response by
binding the ligand and thereby reducing its bioavailability. In the
case of IL-6, the situation is more complex. The receptor consists of
two components, including a ligand-binding 
-subunit (IL-6R, gp80, or
CD126), which in its soluble (s) form (sIL-6R) acts agonistically by
making the ligand accessible to the second subunit, the signal
transducer gp130 (CD130). Soluble forms of both receptor subunits are
present in human blood. Gel filtration of iodinated IL-6 that had been
incubated with human serum revealed that IL-6 is partially trapped in
IL-6/sIL-6R/sgp130 ternary complexes. sgp130 from human plasma was
enriched by immunoaffinity chromatography and identified as a 100-kDa
protein. Functionally equivalent rsgp130 was produced in
baculovirus-infected insect cells to study its antagonistic potential
on four different cell types. It was found that in situations in which
cells lacking membrane-bound IL-6R were stimulated with IL-6/sIL-6R
complexes, sgp130 was a much more potent antagonist than it was
on IL-6R-positive cells stimulated with IL-6 alone. In the latter case,
the neutralizing activity of sgp130 could be markedly enhanced by
addition of sIL-6R. As a consequence of these findings, sIL-6R of human
plasma must be regarded as an antagonistic molecule that enhances the
inhibitory activity of sgp130. Furthermore, in combination with sIL-6R,
sgp130 is a promising candidate for the development of IL-6
antagonists.
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