title: An interleukin 4 (IL-4) mutant protein inhibits both IL-4 or IL-13-induced human immunoglobulin G4 (IgG4) and IgE synthesis and B cell proliferation: support for a common component shared by IL-4 and IL-13 receptors.
abstract: Interleukin 4 (IL-4) and IL-13 share many biological functions. Both cytokines promote growth of activated human B cells and induce naive human surface immunoglobulin D+ (sIgD+) B cells to produce IgG4 and IgE. Here we show that a mutant form of human IL-4, in which the tyrosine residue at position 124 is replaced by aspartic acid (hIL-4.Y124D), specifically blocks IL-4 and IL-13-induced proliferation of B cells costimulated by anti-CD40 mAbs in a dose-dependent fashion. A mouse mutant IL-4 protein (mIL-4.Y119D), which antagonizes the biological activity of mouse IL-4, was ineffective. In addition, hIL-4.Y124D, at concentrations of up to 40 nM, did not affect IL-2-induced B cell proliferation. hIL-4.Y124D did not have detectable agonistic activity in these B cell proliferation assays. Interestingly, hIL-4.Y124D also strongly inhibited both IL-4 or IL-13-induced IgG4 and IgE synthesis in cultures of peripheral blood mononuclear cells, or highly purified sIgD+ B cells cultured in the presence of anti-CD40 mAbs. IL-4 and IL-13-induced IgE responses were inhibited > 95% at a approximately 50- or approximately 20-fold excess of hIL-4.Y124D, respectively, despite the fact that the IL-4 mutant protein had a weak agonistic activity. This agonistic activity was 1.6 +/- 1.9% (n = 4) of the maximal IgE responses induced by saturating concentrations of IL-4. Taken together, these data indicate that there are commonalities between the IL-4 and IL-13 receptor. In addition, since hIL-4.Y124D inhibited both IL-4 and IL-13-induced IgE synthesis, it is likely that antagonistic mutant IL-4 proteins may have potential clinical use in the treatment of IgE-mediated allergic diseases.
authors.affiliation: Human Immunology Department, DNAX Research Institute, Palo Alto, California 94304-1104.
authors.forename: G
authors.initials: G
authors.lastname: Aversa
authors.forename: J
authors.initials: J
authors.lastname: Punnonen
authors.forename: B G
authors.initials: BG
authors.lastname: Cocks
authors.forename: R
authors.initials: R
authors.lastname: de Waal Malefyt
authors.forename: F
authors.initials: F
authors.lastname: Vega
authors.forename: S M
authors.initials: SM
authors.lastname: Zurawski
authors.forename: G
authors.initials: G
authors.lastname: Zurawski
authors.forename: J E
authors.initials: JE
authors.lastname: de Vries
mesh_terms: D015703:Antigens, CD / Q000502:physiology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology; D001402:B-Lymphocytes / Q000502:physiology*; D019013:CD40 Antigens; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007378:Interleukins / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D018123:Receptors, Interleukin / Q000502:physiology*; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000502:physiology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D007074:Immunoglobulin G; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D007378:Interleukins; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D015847:Interleukin-4; D007073:Immunoglobulin E