Eotaxin-1/CC chemokine ligand 11: a novel eosinophil survival factor secreted by human pulmonary artery endothelial cells.
Airway eosinophilia plays a major role in the pathogenesis of asthma with the inhibition of apoptosis by GM-CSF and IL-5 proposed as a mechanism underlying prolonged eosinophil survival. In vivo and ex vivo studies have indicated the capacity of interventions that drive human eosinophil apoptosis to promote the resolution of inflammation. Far less is known about the impact of transendothelial migration on eosinophil survival, in particular, the capacity of endothelial cell-derived factors to contribute toward the apoptosis-resistant phenotype characteristic of airway-resident eosinophils. We examined the effects of conditioned medium from human pulmonary artery endothelial cells (HPAEC-CM) on eosinophil apoptosis in vitro. HPAEC-CM inhibited eosinophil, but not neutrophil apoptosis. This effect was specific to HPAECs and comparable in efficacy to the survival effects of GM-CSF and IL-5. The HPAEC survival factor was shown, on the basis of GM-CSF, IL-5, and IL-3 detection assays, Ab neutralization, and sensitivity to PI3K inhibition, to be clearly discrete from these factors. Gel filtration of HPAEC-CM revealed a peak of eosinophil survival activity at 8-12 kDa, and PCR confirmed the presence of mRNA for CCL5, CCL11, CCL24, CCL26, and CCL27 in the HPAECs. The CCR3 antagonist GW782415 caused a major inhibition of the HPAEC-CM-induced survival effect, and Ab neutralization of individual CCR3 chemokines revealed CCL11 as the major survival factor present in the HPAEC-CM. Furthermore, chemokine Ab arrays demonstrated up-regulation of CCL11 in HPAEC-CM. These data demonstrate the capacity of HPAECs to generate CCR3 agonists and the ability of CCL11 to inhibit human eosinophil apoptosis.
Farahi
Neda
N
Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, UK.
Cowburn
Andrew S
AS
Upton
Paul D
PD
Deighton
John
J
Sobolewski
Anastasia
A
Gherardi
Ermanno
E
Morrell
Nicholas W
NW
Chilvers
Edwin R
ER
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D054413:Chemokine CCL11; D018925:Chemokines / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism*; D017077:Culture Media, Conditioned; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016133:Polymerase Chain Reaction; D011651:Pulmonary Artery / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D018925:Chemokines; D019742:Chemokines, CC; D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019707:Receptors, Chemokine