CXCR3 surface expression in human airway epithelial cells: cell cycle dependence and effect on cell proliferation.
We recently demonstrated that human bronchial epithelial cells (HBEC) constitutively express the CXC chemokine receptor CXCR3, which when activated, induces directed cell migration. The present study in HBEC examined the relative expression of the CXCR3 splice variants CXCR3-A and -B, cell cycle dependence of CXCR3 expression, and the effects of the CXCR3 ligand, the interferon-gamma-inducible CXC chemokine I-TAC/CXCL11, on DNA synthesis and cell proliferation. Both CXCR3-A and -B mRNA, assessed by real-time RT-PCR, were expressed in normal HBEC (NHBEC) and the HBEC line 16-HBE. However, CXCR3-B mRNA was 39- and 6-fold greater than CXCR3-A mRNA in NHBEC and 16-HBE, respectively. Although most HBEC (>80%) assessed by flow cytometry and immunofluorescence microscopy contained intracellular CXCR3, only a minority (<40%) expressed it on the cell surface. In this latter subset of cells, most (>75%) were in the S + G(2)/M phases of the cell cycle. Stimulation of CXCR3 with I-TAC enhanced thymidine incorporation and cell proliferation and increased p38 and ERK1/2 phosphorylation. These data indicate that 1) human airway epithelial cells primarily express CXCR3-B mRNA, 2) surface expression of CXCR3 is largely confined to the S + G(2)/M phases of the cell cycle, and 3) activation of CXCR3 induces DNA synthesis, cell proliferation, and activation of MAPK pathways. We speculate that activation of CXCR3 exerts a mitogenic effect in HBEC, which may be important during airway mucosal injury in obstructive airway diseases such as asthma and chronic obstructive pulmonary disease.
Aksoy
Mark O
MO
Department of Medicine, Division of Pulmonary Disease and Critical Care Medicine, Temple University School of Medicine, Temple University Hospital, 762 Parkinson Pavilion, 3401 N. Broad St., Philadelphia, PA 19140, USA. mark.aksoy@temple.edu
Yang
Yi
Y
Ji
Rong
R
Reddy
P J
PJ
Shahabuddin
Syed
S
Litvin
Judith
J
Rogers
Thomas J
TJ
Kelsen
Steven G
SG
D017398:Alternative Splicing; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D004261:DNA Replication; D016195:G2 Phase; D014644:Genetic Variation; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000235:genetics*; D020545:Respiratory Mucosa / Q000166:cytology* / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C515187:CXCR3 protein, human; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases