Reassessment of interactions between hematopoietic receptors using common beta-chain and interleukin-3–specific receptor beta-chain–null cells: no evidence of functional interactions with receptors for erythropoietin, granulocyte colony-stimulating factor, or stem cell factor

Abstract

AbstractMice lacking both the gene encoding the shared receptor for granulocyte macrophage–colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 common β-chain (Bc) and the gene for the IL-3 specific receptor (BIL3) were generated. This was achieved by targeting the Bc locus in embryonic stem cells that were heterozygous for a null mutation of BIL3. Cells from mice generated with the doubly targeted embryonic stem cells were unresponsive to all 3 cytokines. Considerable previous data suggested a role for common beta-chain (βc) in modulating signaling of cytokines including erythropoietin (EPO), G-CSF, and stem cell factor (SCF). However, bone marrow cells from mice lacking βc and βIL3 showed normal responsiveness to these cytokines. Thus, there was no evidence for a biologically significant interaction between signaling via βc or βIL3 and signaling by EPO, G-CSF, or SCF. Previously documented biochemical phenomena, including receptor transmodulation, receptor transphosphorylation, and even direct physical interaction, involving the βc/βIL-3 receptor systems do not reflect genuine interactions of physiological significance in primary hematopoietic cells. This study provided results that challenge conclusions previously established using a variety of biochemical assays.