SOLUBLE IL-6 RECEPTOR POTENTIATES THE ANTAGONISTIC ACTIVITY OF SOLUBLE GP130 ON IL-6 RESPONSES

Soluble receptors for several cytokines have been detected in body flu ids 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 alpha-subunit (IL-6R, gp80, or CD126), wh ich 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 b lood. Gel filtration of iodinated IL-6 that had been incubated with hu man serum revealed that IL-6 is partially trapped in IL-6/sIL-6R/sgp13 0 ternary complexes. sgp130 from human plasma was enriched by immunoaf finity chromatography and identified as a 100-kDa protein. Functionall y 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 co uld be markedly enhanced by addition of sIL-6R, As a consequence of th ese findings, sIL-6R of human plasma must be regarded as an antagonist ic molecule that enhances the inhibitory activity of sgp130, Furthermo re, in combination with sIL-6R, sgp130 is a promising candidate for th e development of IL-6 antagonists.