Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF

Björn Schuster, Marina Kovaleva, Yi Sun, Petra Regenhard, Vance Matthews, Joachim Grötzinger, Stefan Rose-John, Karl-Josef Kallen, Marina Kovaleva

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

Human ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that exerts a neuroprotective effect in multiple sclerosis and amyotrophic 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 alpha-receptor (CNTFR), which is not involved in signal transduction, and the beta-receptors gp130 and leukemia inhibitory factor receptor (LIFR). Previous studies with rat CNTF demonstrated that rat CNTF is unable to interact with the human interleukin-6 alpha-receptor, whereas at high concentrations, it can directly induce a signaling 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 alpha-receptor and thus widen the target spectrum of human CNTF. Engineering a CNTFR-specific human CNTF variant may therefore be a prerequisite to improving the safety profile of CNTF.
Original languageEnglish
Pages (from-to)9528-35
Number of pages8
JournalThe Journal of Biological Chemistry
Volume278
Issue number11
Publication statusPublished - 14 Mar 2003

Fingerprint

Ciliary Neurotrophic Factor
Interleukin-6 Receptors
Ciliary Neurotrophic Factor Receptor
OSM-LIF Receptors
Rats
Amyotrophic Lateral Sclerosis
Neuroprotective Agents
Signal transduction
Multiple Sclerosis
Signal Transduction
Toxicity
Cytokines

Keywords

  • Animals
  • Biological Assay
  • Cell Division
  • Ciliary Neurotrophic Factor
  • Circular Dichroism
  • Cytokines
  • DNA-Binding Proteins
  • Dimerization
  • Dose-Response Relationship, Drug
  • Humans
  • Interleukin-6
  • Mice
  • Models, Molecular
  • Phosphorylation
  • Protein Binding
  • Rats
  • Receptor, Ciliary Neurotrophic Factor
  • Receptors, Interleukin-6
  • STAT3 Transcription Factor
  • Signal Transduction
  • Surface Plasmon Resonance
  • Time Factors
  • Trans-Activators
  • Transfection
  • Tumor Cells, Cultured

Cite this

Schuster, B., Kovaleva, M., Sun, Y., Regenhard, P., Matthews, V., Grötzinger, J., ... Kovaleva, M. (2003). Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. The Journal of Biological Chemistry, 278(11), 9528-35.

Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. / Schuster, Björn; Kovaleva, Marina; Sun, Yi; Regenhard, Petra; Matthews, Vance; Grötzinger, Joachim; Rose-John, Stefan; Kallen, Karl-Josef; Kovaleva, Marina.

In: The Journal of Biological Chemistry, Vol. 278, No. 11, 14.03.2003, p. 9528-35.

Research output: Contribution to journalArticle

Schuster, B, Kovaleva, M, Sun, Y, Regenhard, P, Matthews, V, Grötzinger, J, Rose-John, S, Kallen, K-J & Kovaleva, M 2003, 'Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF', The Journal of Biological Chemistry, vol. 278, no. 11, pp. 9528-35.
Schuster, Björn ; Kovaleva, Marina ; Sun, Yi ; Regenhard, Petra ; Matthews, Vance ; Grötzinger, Joachim ; Rose-John, Stefan ; Kallen, Karl-Josef ; Kovaleva, Marina. / Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. In: The Journal of Biological Chemistry. 2003 ; Vol. 278, No. 11. pp. 9528-35.
@article{4fdcb9521a6b410cbc0e25056d1da97b,
title = "Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF",
abstract = "Human ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that exerts a neuroprotective effect in multiple sclerosis and amyotrophic 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 alpha-receptor (CNTFR), which is not involved in signal transduction, and the beta-receptors gp130 and leukemia inhibitory factor receptor (LIFR). Previous studies with rat CNTF demonstrated that rat CNTF is unable to interact with the human interleukin-6 alpha-receptor, whereas at high concentrations, it can directly induce a signaling 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 alpha-receptor and thus widen the target spectrum of human CNTF. Engineering a CNTFR-specific human CNTF variant may therefore be a prerequisite to improving the safety profile of CNTF.",
keywords = "Animals, Biological Assay, Cell Division, Ciliary Neurotrophic Factor, Circular Dichroism, Cytokines, DNA-Binding Proteins, Dimerization, Dose-Response Relationship, Drug, Humans, Interleukin-6, Mice, Models, Molecular, Phosphorylation, Protein Binding, Rats, Receptor, Ciliary Neurotrophic Factor, Receptors, Interleukin-6, STAT3 Transcription Factor, Signal Transduction, Surface Plasmon Resonance, Time Factors, Trans-Activators, Transfection, Tumor Cells, Cultured",
author = "Bj{\"o}rn Schuster and Marina Kovaleva and Yi Sun and Petra Regenhard and Vance Matthews and Joachim Gr{\"o}tzinger and Stefan Rose-John and Karl-Josef Kallen and Marina Kovaleva",
year = "2003",
month = "3",
day = "14",
language = "English",
volume = "278",
pages = "9528--35",
journal = "The Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC",
number = "11",

}

TY - JOUR

T1 - Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF

AU - Schuster, Björn

AU - Kovaleva, Marina

AU - Sun, Yi

AU - Regenhard, Petra

AU - Matthews, Vance

AU - Grötzinger, Joachim

AU - Rose-John, Stefan

AU - Kallen, Karl-Josef

AU - Kovaleva, Marina

PY - 2003/3/14

Y1 - 2003/3/14

N2 - Human ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that exerts a neuroprotective effect in multiple sclerosis and amyotrophic 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 alpha-receptor (CNTFR), which is not involved in signal transduction, and the beta-receptors gp130 and leukemia inhibitory factor receptor (LIFR). Previous studies with rat CNTF demonstrated that rat CNTF is unable to interact with the human interleukin-6 alpha-receptor, whereas at high concentrations, it can directly induce a signaling 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 alpha-receptor and thus widen the target spectrum of human CNTF. Engineering a CNTFR-specific human CNTF variant may therefore be a prerequisite to improving the safety profile of CNTF.

AB - Human ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that exerts a neuroprotective effect in multiple sclerosis and amyotrophic 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 alpha-receptor (CNTFR), which is not involved in signal transduction, and the beta-receptors gp130 and leukemia inhibitory factor receptor (LIFR). Previous studies with rat CNTF demonstrated that rat CNTF is unable to interact with the human interleukin-6 alpha-receptor, whereas at high concentrations, it can directly induce a signaling 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 alpha-receptor and thus widen the target spectrum of human CNTF. Engineering a CNTFR-specific human CNTF variant may therefore be a prerequisite to improving the safety profile of CNTF.

KW - Animals

KW - Biological Assay

KW - Cell Division

KW - Ciliary Neurotrophic Factor

KW - Circular Dichroism

KW - Cytokines

KW - DNA-Binding Proteins

KW - Dimerization

KW - Dose-Response Relationship, Drug

KW - Humans

KW - Interleukin-6

KW - Mice

KW - Models, Molecular

KW - Phosphorylation

KW - Protein Binding

KW - Rats

KW - Receptor, Ciliary Neurotrophic Factor

KW - Receptors, Interleukin-6

KW - STAT3 Transcription Factor

KW - Signal Transduction

KW - Surface Plasmon Resonance

KW - Time Factors

KW - Trans-Activators

KW - Transfection

KW - Tumor Cells, Cultured

M3 - Article

VL - 278

SP - 9528

EP - 9535

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

SN - 0021-9258

IS - 11

ER -