Characterization of a potent human interleukin-11 agonist.
Human interleukin-11 (hIL-11) is a multi-potential cytokine that is involved in numerous biological activities, such as haematopoiesis, osteoclastogenesis, neurogenesis and female fertility, and also displays anti-inflammatory properties. IL-11 is used clinically to treat chemotherapy-induced thrombocytopenia. Because of its broad spectrum of action, improved IL-11 agonists, as well as IL-11 antagonists, could be of interest for numerous clinical applications. IL-11 signalling is dependent on the formation of a tripartite ligand-receptor complex consisting of IL-11, the IL-11R (IL-11 receptor) alpha subunit (responsible for the specificity of the interaction) and gp130 (glycoprotein 130) receptor beta subunit (responsible for signal transduction). The interaction between IL-11 and IL-11Ralpha subunit occurs at its recently assigned site I. We have designed an IL-11 mutein whose hydrophobicity at site I has been increased. The mutein has been characterized in terms of structure, affinity, specificity and bioactivity. Electrophoretic analysis, gel filtration, IR spectroscopy and CD indicate that this new protein is more compact than wild-type IL-11. It binds to IL-11Ralpha with a three-fold-enhanced affinity, and retains the ability to recruit gp130 through site II. However, analysis of its biological activity revealed a complex pattern: although this mutein is 60-400-fold more active than wild-type IL-11 on the proliferation of 7TD1 murine hybridoma cell, it is less active than IL-11 on the proliferation of B9 cells, another murine hybridoma cell line. The results are interpreted on the basis of an IL-11 conformational change induced by the mutations, and the preferential use by the mutein of another unknown transducing receptor chain.
Harmegnies
Dimitri
D
Institut Pasteur de Bruxelles, rue Engeland 642, B-1180 Brussels, Belgium.
Wang
Xiao-Ming
XM
Vandenbussche
Paul
P
Leon
Arnaud
A
Vusio
Patricia
P
Grötzinger
Joachim
J
Jacques
Yannick
Y
Goormaghtigh
Erik
E
Devreese
Bart
B
Content
Jean
J
D000818:Animals; D001224:Aspartic Acid / Q000235:genetics / Q000502:physiology; D002455:Cell Division; D002460:Cell Line; D002942:Circular Dichroism; D006639:Histidine / Q000235:genetics / Q000502:physiology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D017370:Interleukin-11 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D053703:Interleukin-11 Receptor alpha Subunit; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D018123:Receptors, Interleukin / Q000819:agonists* / Q000378:metabolism; D053702:Receptors, Interleukin-11; D013055:Spectrophotometry, Infrared
C508428:IL11RA protein, human; C508429:Il11ra1 protein, mouse; C508431:Il11ra2 protein, mouse; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D001224:Aspartic Acid; D006639:Histidine