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

Mice lacking both the gene encoding the shared receptor for granulocyte mac rophage-colony-stimulating factor (GMCSF), interleukin-3 (IL-3), and IL-5 c ommon beta-chain (B-c) and the gene for the IL-3 specific receptor (BIL3) w ere generated. This was achieved by targeting the B-c locus in embryonic st em cells that were heterozygous for a null mutation of BIL3. Cells from mic e generated with the doubly targeted embryonic stem cells were unresponsive to all 3 cytokines. Considerable previous data suggested a role for common beta-chain (beta(c)) in modulating signaling of cytokines including erythr opoietin (EPO), G-CSF, and stem cell factor (SCF). However, bone marrow cel ls from mice lacking beta(c) and beta(IL3) showed normal responsiveness to these cytokines. Thus, there was no evidence for a biologically significant interaction between signaling via beta(c) or beta(IL3) and signaling by EP O, G-CSF, or SCF. Previously documented biochemical phenomena, including re ceptor transmodulation, receptor transphosphorylation, and even direct phys ical interaction, involving the beta(c)/beta IL-3 receptor systems do not r eflect genuine interactions of physiological significance in primary hemato poietic cells. This study provided results that challenge conclusions previ ously established using a variety of biochemical assays. (Blood. 2000;96:15 88-1590) (C) 2000 by The American Society of Hematology.