Species-specific agonist/antagonist activities of human interleukin-4 variants suggest distinct ligand binding properties of human and murine common receptor gamma chain.
Interleukin-4 (IL-4) is a pleiotropic cytokine eliciting various responses in target cells upon binding to its receptor. Activation of the IL-4 receptor probably involves interaction of the ligand with both the IL-4 receptor alpha subunit (IL-4R alpha) and the common gamma chain (c gamma). Although human and murine IL-4 receptor alpha chains are specific for IL-4 from the same species, murine c gamma can form a signal-competent complex with human IL-4R alpha (hIL-4R alpha) and human IL-4 (hIL-4). We have generated a hIL-4 responsive murine myeloid cell line (FDC-4G) expressing a chimera comprising the extracellular domain of human IL-4R alpha and the intracellular domain of human granulocyte colony-stimulating factor receptor (hG-CSFR). This hybrid receptor was shown to form a complex with hIL-4 and the murine c gamma-chain. Biological activities of human IL-4 variants on murine FDC-4G cells and on the human erythroleukemic cell line TF-1 displayed a strikingly different pattern. Single amino acid replacements at two different positions in the C-terminal helix of hIL-4, the region of the previously defined "signaling site," lead to an inverse agonist/antagonist behavior of the resulting cytokines in the two cellular systems. From these findings we conclude that upon formation of the activated IL-4 receptor complex murine and human c gamma interact with hIL-4 in a geometrically different fashion.
Bönsch
D
D
Theodor-Boveri-Institut für Biowissenschaften (Biozentrum), Universität Würzburg, Federal Republic of Germany.
Kammer
W
W
Lischke
A
A
Friedrich
K
K
D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics; D016415:Sequence Alignment; D015398:Signal Transduction; D013045:Species Specificity
D017931:DNA Primers; D008024:Ligands; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D015847:Interleukin-4; D001120:Arginine