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*
Laboratory of Medical Allergology, Allergy Unit, and
Laboratory for Tissue Typing, Department of Clinical Immunology, National University Hospital, Copenhagen, Denmark; and
Department of Immunology, Anhui Medical University, People’s Republic of China
CXCR3, known to have four ligands (IFN-
inducible
protein 10 ( IP-10), monokine induced by IFN- (Mig), I-TAC, and
6Ckine), is predominately expressed on memory/activated T
lymphocytes. We recently reported that GM-CSF induces CXCR3 expression
on CD34+ hemopoietic progenitors, in which 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. IP-10 and Mig can induce Syk, Cbl, and
Cbl-b phosphorylation in CD34+ progenitors by means of
CXCR3. IP-10 or Mig has induced neither chemotaxis nor adhesion in
GM-CSF-stimulated Cbl-b-blocked CD34+ hemopoietic
progenitors, whereas SDF-1
induces both chemotaxis and adhesion in
these cells. Interestingly, 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 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/ 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.
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