A murine interleukin-4 antagonistic mutant protein completely inhibits interleukin-4-induced cell proliferation, differentiation, and signal transduction.
We characterize here a highly efficient antagonist for interleukin-4 (IL-4) in the mouse system. In this double mutant of the murine IL-4 protein, both glutamine 116 and tyrosine 119 were substituted by aspartic acid residues. This variant (QY) bound with similar affinity to the IL-4 receptor alpha subunit as wild type IL-4 without inducing cellular responses. In contrast, QY completely inhibited in a dose-dependent manner the IL-4-induced proliferation of lipopolysaccharide-stimulated murine splenic B-cells, of the murine T cell line CTLL-2, and of the murine pre-B-cell line BA/F3. QY also inhibited the IL-4-stimulated up-regulation of CD23 expression by lipopolysaccharide-stimulated murine splenic B-cells and abolished tyrosine phosphorylation of the transcription factor Stat6 and the tyrosine kinase Jak3 in IL-4-stimulated BA/F3 cells. Selective inhibition of IL-4 may be beneficial in T-helper cell type 2-dominated diseases, like type I hypersensitivity reactions or helminthic infections. The QY mutant could be an attractive tool to study in vivo the therapeutic potential of IL-4 antagonists in mouse systems.
Grunewald
S M
SM
Theodor-Boveri-Institut für Biowissenschaften (Biozentrum), Physiologische Chemie II, Am Hubland, D-97074 Würzburg, Germany.
Kunzmann
S
S
Schnarr
B
B
Ezernieks
J
J
Sebald
W
W
Duschl
A
A
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D017924:Nucleopolyhedroviruses / Q000235:genetics; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D018411:Spodoptera
D015703:Antigens, CD; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D015847:Interleukin-4