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 pr otein, both glutamine 116 and tyrosine 119 were substituted by asparti c acid residues. This variant (QY) bound with similar affinity to the IL-4 receptor alpha subunit as wild type IL-4 without inducing cellula r 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 transcr iption 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 t o study in vivo the therapeutic potential of IL-4 antagonists in mouse systems.