DIFFERENT HUMAN INTERLEUKIN-4 MUTANTS PREFERENTIALLY ACTIVATE HUMAN OR MURINE COMMON RECEPTOR-GAMMA CHAIN

Interleukin-4 (IL-4) shows species-specific activity due to species-re stricted interaction with the IL-4 receptor alpha (IL-4R alpha) chain. The second subunit of a functional IL-4 receptor, the common gamma ch ain (gamma(c)), is more promiscuous, since human IL-4 is able to activ ate IL-4 receptor complexes containing either human or murine common g amma receptor chain (gamma(c)). We have stably transfected factor-depe ndent mouse cells of myeloid and lymphoid origin with combinations of human TL-4R alpha and gamma(c) derivatives. In these cell lines, both human and murine gamma(c) receptors as well as IL-4R alpha chains from both species are simultaneously expressed. Both versions of gamma(c) readily form ternary complexes with either human IL-4 and human IL-4R alpha or murine IL-4 and murine IL-4R alpha. Due to distinct Ligand-bi nding properties of human and murine gamma(c), the two receptor comple xes can be activated preferentially by different mutant variants of hu man IL-4. The contribution of murine common gamma chain to human IL-4- induced signal transduction is suppressed by an inhibitory antibody di rected to the extracellular domain of the mouse gamma(c). We present e vidence that the two IL-4R complexes functionally interfere with each other and compete for response-limiting signalling components