Antagonistic mutant proteins of interleukin-4.
Interleukin-4 is a major regulator of the immune system, directing e.g. induction of a TH2 phenotype in T-cells, activation of B-cells and synthesis of IgE type antibodies, which are associated with allergic responses. Site-directed mutagenesis has revealed two sites important for receptor interaction on IL-4: site I mediates binding to the IL-4 receptor alpha subunit, and site II is involved in signal transduction through the receptor complex. Specific mutations in site II produced a series of ligands which bound to the receptor with high affinity, but had little or no agonistic activity and inhibited effects of wild type IL-4. The closely related cytokine IL-13, also a mediator of allergic processes, is antagonized as well. Antagonistic site II mutants of human IL-4 are therefore effective inhibitors with therapeutic potential for IL-4 associated diseases like type I hypersensitivity and asthma.
Duschl
A
A
Theodor-Boveri-Institut für Biowissenschaften, Universität Würzburg, Germany.
Müller
T
T
Sebald
W
W
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001249:Asthma / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D001665:Binding Sites; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007073:Immunoglobulin E / Q000096:biosynthesis; D015847:Interleukin-4 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D017433:Protein Structure, Secondary; D018123:Receptors, Interleukin / Q000276:immunology / Q000378:metabolism*; D019948:Receptors, Interleukin-4; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D046911:Macromolecular Substances; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D007073:Immunoglobulin E