CXCR3 chemokine receptor-induced chemotaxis in human airway epithelial cells: role of p38 MAPK and PI3K signaling pathways.
Human airway epithelial cells (HAEC) constitutively express the CXC chemokine receptor CXCR3, which regulates epithelial cell movement. In diseases such as chronic obstructive pulmonary disease and asthma, characterized by denudation of the epithelial lining, epithelial cell migration may contribute to airway repair and reconstitution. This study compared the potency and efficacy of three CXCR3 ligands, I-TAC/CXCL11, IP-10/CXCL10, and Mig/CXCL9, as inducers of chemotaxis in HAEC and examined the underlying signaling pathways involved. Studies were performed in cultured HAEC from normal subjects and the 16-HBE cell line. In normal HAEC, the efficacy of I-TAC-induced chemotaxis was 349 +/- 88% (mean +/- SE) of the medium control and approximately one-half the response to epidermal growth factor, a highly potent chemoattractant. In normal HAEC, Mig, IP-10, and I-TAC induced chemotaxis with similar potency and a rank order of efficacy of I-TAC = IP-10 > Mig. Preincubation with pertussis toxin completely blocked CXCR3-induced migration. Of interest, intracellular [Ca(2+)] did not rise in response to I-TAC, IP-10, or Mig. I-TAC induced a rapid phosphorylation (5-10 min) of two of the three MAPKs, i.e., p38 and ERK1/2. Pretreatment of HAEC with the p38 inhibitor SB 20358 or the PI3K inhibitor wortmannin dose-dependently inhibited the chemotactic response to I-TAC. In contrast, the ERK1/2 inhibitor U0126 had no effect on chemotaxis. These data indicate that in HAEC, CXCR3-mediated chemotaxis involves a G protein, which activates both the p38 MAPK and PI3K pathways in a calcium-independent fashion.
Shahabuddin
Syed
S
Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Ji
Rong
R
Wang
Ping
P
Brailoiu
Eugene
E
Dun
Na
N
Yang
Yi
Y
Aksoy
Mark O
MO
Kelsen
Steven G
SG
D001980:Bronchi / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000819:agonists / Q000502:physiology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
C515187:CXCR3 protein, human; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases