Specific antagonism of type I IL-4 receptor with a mutated form of murine IL-4.
IL-4 is a pleiotropic cytokine that is essential for the differentiation of Th2 cells and is critically involved in the pathogenesis of certain infectious and allergic diseases. We have produced and functionally characterized a mutant of murine IL-4 (IL-4.Y119D) as a potential antagonist of IL-4. The analysis of IL-4R binding revealed no differences between wild-type and mutated IL-4. Despite this finding, IL-4.Y119D was unable to induce proliferation of several IL-4-responsive T cell lines mediated via the type I IL-4R (IL-4Ralpha/common gamma chain (gamma c chain)) and specifically inhibited the proliferative effect of wild-type IL-4. In contrast, with IL-4.Y119D we found induction of MHC class II and CD23 molecules on resting splenic B cells as well as proliferation of B9 plasmocytoma cells. In addition, IL-4.Y119D induced mRNA for soluble IL-4R, leading to the release of soluble IL-4R protein by spleen cells. In macrophages, mutated IL-4 in combination with IFN-gamma induced TNF-alpha-dependent killing of Leishmania major parasites such as wild-type IL-4. The agonistic effects of IL-4.Y119D were observed on cells expressing the IL-13R alpha-chain, including an IL-13R alpha-chain transfected T cell line, but were absent in T cells that lack this molecule, indicating that IL-4.Y119D conveys its activity via the type II IL-4R (IL-4Ralpha/IL-13Ralpha). The described IL-4 mutant, therefore, represents a new tool to use in dissecting different IL-4 functions that are mediated by either type I or type II IL-4R complexes.
Institut für Klinische Mikrobiologie, Immunologie, und Hygiene der Universität Erlangen-Nürnberg, Germany.
M
M
Schnare
H
H
Blum
S
S
Jüttner
M
M
Röllinghoff
A
A
Gessner
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005260:Female; D006133:Growth Substances / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D018793:Interleukin-13 / Q000378:metabolism; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D007399:Interphase / Q000235:genetics / Q000276:immunology; D018320:Leishmania major / Q000254:growth & development / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding / Q000276:immunology; D017455:Receptors, IgE / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014162:Transfection / Q000276:immunology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000235:genetics
D006133:Growth Substances; D000949:Histocompatibility Antigens Class II; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D017455:Receptors, IgE; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D001224:Aspartic Acid; D014443:Tyrosine