CXCR4 undergoes complex lineage and inducing agent-dependent dissociation of expression and functional responsiveness...

The CXC chemokine SDF-1 and its receptor CXCR4 mediate myelopoiesis, presumably by regulating the homing of hematopoietic progenitor 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 different measures of CXCR4 expression and functional coupling: mRNA and surface expression, SDF-1-mediated [(35)S]GTPgammaS binding, calcium flux, and chemotaxis were examined simultaneously. Granulocytic differentiation with dimethyl sulfoxide induced surface expression of CXCR4 as well as SDF-1-mediated [(35)S]GTPgammaS binding and chemotaxis, whereas calcium flux was attenuated by twofold to threefold in HL-60 cells. Conversely, monocytic differentiation with vitamin D(3) inhibited surface expression and SDF-1-mediated chemotaxis, even as it induced [(35)S]GTPgammaS 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 involvement of different G-proteins for signal transduction during cellular differentiation and following activation with SDF-1.