CXCR4 undergoes complex lineage and inducing agent-dependent dissociation of expression and functional responsiveness to SDF-1alpha during myeloid differentiation.
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.
Gupta
S K
SK
Department of Cardiovascular Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. Shalley_K_Gupta@sbphrd.com
Pillarisetti
K
K
Aiyar
N
N
D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis; D004305:Dose-Response Relationship, Drug; D006098:Granulocytes / Q000166:cytology / Q000276:immunology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007700:Kinetics; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002118:Calcium