title: Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common gamma chain.
abstract: Interleukin-4 (IL-4) and IL-13 exert similar, nonadditive effects on endothelial cells, inducing vascular cell adhesion molecule-1 (VCAM-1) expression and subsequent transmigration of eosinophils. The receptor for IL-4 and IL-13 was described as a shared heteromultimeric complex in which the common gamma-chain (gamma c) subunit was essential for activity. Endothelial cell bound both cytokines with high affinity; by flow cytofluorometry and reverse transcription-polymerase chain reaction (RT-PCR), they expressed IL-4 receptor alpha (IL-4R alpha) but did not express the gamma c of the IL-2R. Radioligand cross-linking experiments followed by immunoprecipitation with the monoclonal antibody (MoAb) S697 to the IL-4R alpha showed IL-4-specific binding at 130 kD, the IL-4R alpha, and to a minor extent to a double band coimmunoprecipitated at 65 to 75 kD. [125 I]IL-13 bound predominantly to the 65- to 75- kD band and with a trace amount of binding at 130 kD. However, no ligand-cross-linked receptor was precipitated by the MoAb S697, indicating a cognate novel IL-13-binding subunit. Excess unlabeled IL-4 completely displaced IL-13 binding. Similarly, nonsignaling IL-4 (Y124D)-mutant abolished IL-4- and IL-13-mediated signal transduction. Unlabeled IL-13 competed successfully for IL-4 binding at 65 to 75 kD but was unable to completely displace Il-4 from its binding to the IL-4R alpha. The MoAb TUGh4, specific for the gamma c, failed to precipitate ligand-cross-linked IL-4R and IL-13R. Therefore, the subunit structure of the functional receptors for IL-4 and IL-13 on human endothelial cells does not use or require the common gamma c of the IL-2R.
authors.affiliation: Department of Pharmacy, Biopharmacy, Federal Institute of Technology, Zurich, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Schnyder
authors.forename: S
authors.initials: S
authors.lastname: Lugli
authors.forename: N
authors.initials: N
authors.lastname: Feng
authors.forename: H
authors.initials: H
authors.lastname: Etter
authors.forename: R A
authors.initials: RA
authors.lastname: Lutz
authors.forename: B
authors.initials: B
authors.lastname: Ryffel
authors.forename: K
authors.initials: K
authors.lastname: Sugamura
authors.forename: H
authors.initials: H
authors.lastname: Wunderli-Allenspach
authors.forename: R
authors.initials: R
authors.lastname: Moser
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001667:Binding, Competitive; D016466:CHO Cells; D002461:Cell Line, Transformed; D006224:Cricetinae; D003412:Cricetulus; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism* / Q000494:pharmacology; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053660:Receptors, Interleukin-13; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D019948:Receptors, Interleukin-4; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D015703:Antigens, CD; D004791:Enzyme Inhibitors; C508181:IL13RA1 protein, human; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D047428:Protein Kinase Inhibitors; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D015375:Receptors, Interleukin-2; D019948:Receptors, Interleukin-4; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4