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A fusion protein of the gp130 and interleukin-6Ralpha ligand-binding domains acts as a potent interleukin-6 inhibitor.
Ancey, Cecile; Kuster, Andrea; Haan, Serge et al.
2003In Journal of Biological Chemistry, 278 (19), p. 16968-72
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Keywords :
Animals; Antigens, CD/genetics/metabolism; Cytokine Receptor gp130; Interleukin-6/antagonists & inhibitors; Ligands; Membrane Glycoproteins/genetics/metabolism; Protein Structure, Tertiary; Receptors, Interleukin-6/genetics/metabolism; Recombinant Fusion Proteins/genetics/metabolism; Signal Transduction
Abstract :
[en] Interleukin (IL)-6 is involved in the maintenance and progression of several diseases such as multiple myeloma, rheumatoid arthritis, or osteoporosis. The present work aims at the development of an IL-6 inhibitor for the use in anti-cytokine therapies. The IL-6 receptor is composed of two different subunits, an alpha-subunit (IL-6Ralpha) that binds IL-6 with low affinity and a beta-subunit (gp130) that binds the IL-6.IL-6Ralpha complex with high affinity and as a result triggers intracellular signaling. In its soluble form, gp130 is a natural antagonist that neutralizes IL-6.soluble IL-6Ralpha complexes. It was our strategy to appropriately fuse the two receptor subunit fragments involved in IL-6 receptor complex formation to bind IL-6 with high affinity and to antagonize its effects. The ligand-binding domains of gp130 (D1-D2-D3) and IL-6Ralpha (D2-D3) were connected using three different linkers. The resulting constructs were expressed in stably transfected insect cells and tested for their ability to inhibit IL-6 activity in several in vitro systems. All fusion proteins were strong inhibitors of IL-6 signaling and abrogated IL-6-induced phosphorylation of STAT3, proliferation of transfected Ba/F3 cells, and induction of acute-phase protein synthesis. As intended, the fused receptors were much more effective than the separately expressed soluble receptor proteins. The fusion protein strategy presented here can also be applied to other cytokines that signal via receptors composed of two different subunits to design new potent inhibitors for anti-cytokine therapies.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Ancey, Cecile
Kuster, Andrea
Haan, Serge ;  Rheinisch - Westfälische Technische Hochschule Aachen - RWTH > Institute for Biochemistry
Herrmann, Andreas
Heinrich, Peter C.
Muller-Newen, Gerhard
External co-authors :
yes
Language :
English
Title :
A fusion protein of the gp130 and interleukin-6Ralpha ligand-binding domains acts as a potent interleukin-6 inhibitor.
Publication date :
2003
Journal title :
Journal of Biological Chemistry
ISSN :
1083-351X
Publisher :
American Society for Biochemistry and Molecular Biology, United States - Maryland
Volume :
278
Issue :
19
Pages :
16968-72
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 26 April 2013

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