I. Kurth et al., Activation of the signal transducer glycoprotein 130 by both IL-6 and IL-11 requires two distinct binding epitopes, J IMMUNOL, 162(3), 1999, pp. 1480-1487
The coordination and regulation of immune responses are primarily mediated
by cytokines that bind to specific cell surface receptors. Glycoprotein 130
(gp130) belongs to the family of class I cytokine receptors and is the com
mon signal-transducing receptor submit shared by the so-called IL-6 type cy
tokines (IL-6, IL-11, ciliary neurotrophic factor, leukemia inhibitory fact
or, oncostatin M, and cardiotrophin-1). The inflammatory cytokines IL-6 and
IL-11 induce gp130 homodimerization after binding to their specific cu rec
eptors, which leads to the activation of the Janus kinase/STAT signal trans
duction pathway. A molecular model of IL-6/IL-6R/gp130, which is based on t
he structure of the growth hormone/growth hormone receptor complex, allowed
the selection of several amino acids located in the cytokine-binding modul
e of gp130 for mutagenesis, The mutants were analyzed with regard to IL-6-
or IL-11-induced STAT activation and ligand binding. It was found that Y190
and F191 are essential for the interaction of gp130 with IL-6 as well as I
L-11, suggesting a common mode of recognition of helical cytokines by class
I cytokine receptors. Furthermore, the requirement of the gp130 N-terminal
Ig-like domain for ligand binding and signal transduction was demonstrated
by the use of deletion mutants. Thus, besides the observed analog to the g
rowth hormone/growth hormone receptor complex, there is a substantial diffe
rence in the mechanism of receptor engagement by cytokines that signal via
gp130.