CXCR3 expression on CD34(+) hemopoietic progenitors induced by granulocyte-macrophage colony-stimulating factor: II. Signaling pathways involved.
CXCR3, known to have four ligands (IFN-gamma inducible protein 10 (gamma IP-10), monokine induced by IFN-gamma (Mig), I-TAC, and 6Ckine), is predominantly expressed on memory/activated T lymphocytes. We recently reported that GM-CSF induces CXCR3 expression on CD34(+) hemopoietic progenitors, in which gamma IP-10 and Mig induce chemotaxis and adhesion. Here we further report that stimulation with GM-CSF causes phosphorylation of Syk protein kinase, but neither Casitas B-lineage lymphoma (Cbl) nor Cbl-b in CD34(+) hemopoietic progenitors can be blocked by anti-CD116 mAb. Specific Syk blocking generated by PNA antisense completely inhibits GM-CSF-induced CXCR3 expression in CD34(+) progenitors at both mRNA and protein as well as at functional levels (chemotaxis and adhesion). Cbl and Cbl-b blocking have no such effects. Thus, GM-CSF binds to its receptor CD116, and consequently activates Syk phosphorylation, which leads to induce CXCR3 expression. gamma IP-10 and Mig can induce Syk, Cbl, and Cbl-b phosphorylation in CD34(+) progenitors by means of CXCR3. gamma IP-10 or Mig has induced neither chemotaxis nor adhesion in GM-CSF-stimulated Cbl-b-blocked CD34(+) hemopoietic progenitors, whereas SDF-1alpha induces both chemotaxis and adhesion in these cells. Interestingly, gamma IP-10 and Mig can induce chemotaxis and adhesion in GM-CSF-stimulated Syk- or Cbl-blocked CD34(+) hemopoietic progenitors. Thus, Cbl-b, but not Syk and Cbl phosphorylation, is essential for gamma IP-10- and Mig-induced chemotaxis and adhesion in CD34(+) hemopoietic progenitors. This study provides a useful insight into novel signaling transduction pathways of the functions of CXCR3/gamma IP-10 and Mig, which may be especially important in the cytokine/chemokine environment for mobilization, homing, and recruitment during proliferation, differentiation, and maturation of hemopoietic progenitor cells.
Jinquan
T
T
Laboratory of Medical Allergology, Allergy Unit, Department of Clinical Immunology, National University Hospital, Copenhagen, Denmark. TAN@RH.DK
Anting
L
L
Jacobi
H H
HH
Glue
C
C
Jing
C
C
Ryder
L P
LP
Madsen
H O
HO
Svejgaard
A
A
Skov
P S
PS
Malling
H J
HJ
Poulsen
L K
LK
D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34 / Q000302:isolation & purification*; D002352:Carrier Proteins; D002448:Cell Adhesion; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D002633:Chemotaxis; D004792:Enzyme Precursors; D005312:Fetal Blood / Q000166:cytology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D050721:Proto-Oncogene Proteins c-cbl; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D015398:Signal Transduction; D000072377:Syk Kinase; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D002352:Carrier Proteins; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D004792:Enzyme Precursors; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase