Human type II pneumocyte chemotactic responses to CXCR3 activation are mediated by splice variant A.
Chemokine receptors control several fundamental cellular processes in both hematopoietic and structural cells, including directed cell movement, i.e., chemotaxis, cell differentiation, and proliferation. We have previously demonstrated that CXCR3, the chemokine receptor expressed by Th1/Tc1 inflammatory cells present in the lung, is also expressed by human airway epithelial cells. In airway epithelial cells, activation of CXCR3 induces airway epithelial cell movement and proliferation, processes that underlie lung repair. The present study examined the expression and function of CXCR3 in human alveolar type II pneumocytes, whose destruction causes emphysema. CXCR3 was present in human fetal and adult type II pneumocytes as assessed by immunocytochemistry, immunohistochemistry, and Western blotting. CXCR3-A and -B splice variant mRNA was present constitutively in cultured type II cells, but levels of CXCR3-B greatly exceeded CXCR3-A mRNA. In cultured type II cells, I-TAC, IP-10, and Mig induced chemotaxis. Overexpression of CXCR3-A in the A549 pneumocyte cell line produced robust chemotactic responses to I-TAC and IP-10. In contrast, I-TAC did not induce chemotactic responses in CXCR3-B and mock-transfected cells. Finally, I-TAC increased cytosolic Ca(2+) and activated the extracellular signal-regulated kinase, p38, and phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B kinases only in CXCR3-A-transfected cells. These data indicate that the CXCR3 receptor is expressed by human type II pneumocytes, and the CXCR3-A splice variant mediates chemotactic responses possibly through Ca(2+) activation of both mitogen-activated protein kinase and PI 3-kinase signaling pathways. Expression of CXCR3 in alveolar epithelial cells may be important in pneumocyte repair from injury.
Ji
Rong
R
Division of Pulmonary Disease and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Lee
Clement M
CM
Gonzales
Linda W
LW
Yang
Yi
Y
Aksoy
Mark O
MO
Wang
Ping
P
Brailoiu
Eugen
E
Dun
Nae
N
Hurford
Matthew T
MT
Kelsen
Steven G
SG
D000328:Adult; D017398:Alternative Splicing; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000196:embryology / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011014:Pneumonia / Q000503:physiopathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C515187:CXCR3 protein, human; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium