CXCR4 undergoes complex lineage and inducing agent-dependent dissociation of expression and functional responsiveness to SDF-1α during myeloid differentiation

The CXC chemokine SDF-1 and its re- ceptor CXCR4 mediate myelopoiesis, presumably by regulating the homing of hematopoietic progen- itor cells. We used the inducible HL-60 cell line as a model system for comparative analysis of CXCR4 expression during differential maturation into the granulocytic or monocytic phenotypes. Five differ- ent measures of CXCR4 expression and functional coupling: mRNA and surface expression, SDF-1- mediated ( 35 S)GTPgS binding, calcium flux, and chemotaxis were examined simultaneously. Granu- locytic differentiation with dimethyl sulfoxide in- duced surface expression of CXCR4 as well as SDF-1-mediated ( 35 S)GTPgS binding and chemo- taxis, whereas calcium flux was attenuated by two- fold to threefold in HL-60 cells. Conversely, mono- cytic differentiation with vitamin D 3 inhibited sur- face expression and SDF-1-mediated chemotaxis, even as it induced ( 35 S)GTPgS binding and calcium flux by more than twofold. Sodium butyrate up- regulated all parameters of CXCR4 expression studied. Together, these results demonstrate that CXCR4 expression undergoes complex regulation at multiple checkpoints, with the likely involve- ment of different G-proteins for signal transduction during cellular differentiation and following activa- tion with SDF-1. J. Leukoc. Biol. 70: 431-438; 2001.