SPECIES-SPECIFIC AGONIST-ANTAGONIST ACTIVITIES OF HUMAN INTERLEUKIN-4VARIANTS SUGGEST DISTINCT LIGAND-BINDING PROPERTIES OF HUMAN AND MURINE COMMON RECEPTOR-GAMMA CHAIN

Interleukin-4 (IL-4) is a pleiotropic cytokine eliciting various respo nses in target cells upon binding to its receptor. Activation of the I L-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 sp ecific for IL-4 from the same species, murine c gamma can form a signa l-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 l ine (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 wa s shown to form a complex with hIL-4 and the murine c gamma-chain. Bio logical activities of human IL-4 variants on murine FDC-4G cells and o n the human erythroleukemic cell line TF-1 displayed a strikingly diff erent pattern. Single amino acid replacements at two different positio ns in the C-terminal helix of hIL-4, the region of the previously defi ned ''signaling site,'' lead to an inverse agonist/antagonist behavior of the resulting cytokines in the two cellular systems. From these fi ndings we conclude that upon formation of the activated IL-4 receptor complex murine and human c gamma interact with hIL-4 in a geometricall y different fashion.