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J Biol Chem 2003 Jan 6
Schuster B, Kovaleva M, Sun Y, Regenhard P, Matthews V, Grotzinger J, Rose-John S, Kallen KJ.
Biochemisches Institut, Christian-Albrechts-Universitt Kiel, Kiel 24118.
Human ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that exerts a neuroprotective effect in multiple sclerosis and amyotropic lateral sclerosis.
Clinical application of human CNTF, however, was prevented by high toxicity at higher dosages.
Human CNTF elicits cellular responses by induction of a receptor complex consisting of the CNTF a-receptor (CNTFR), which is not involved in signal transduction, and the b-receptors gp130 and leukaemia inhibitory factor receptor (LIFR).
Previous studies with rat CNTF demonstrated that rat CNTF is unable to interact with the human interleukin-6 a-receptor, whereas at high concentrations, it can directly induce a signalling heterodimer of human gp130 and human LIFR in the absence of the CNTF receptor.
Here, we demonstrate that human CNTF cannot directly induce a heterodimer of human gp130 and LIFR.
However, human CNTF can use both, the membrane bound and the soluble human IL-6R, as a substitute for its cognate a-receptor and thus widen the target spectrum of human CNTF.
Engineering a CNTFR specific human CNTF variant may therefore be a prerequisite to improve the safety profile of CNTF.