Upper airway epithelial cells support eosinophil survival in vitro through production of GM-CSF and prostaglandin E2: regulation by glucocorticoids and TNF-alpha.
Production of GM-CSF by epithelial cells has been implicated in eosinophil survival within the airways, although GM-CSF promotes neutrophil and monocyte survival as well. Using primary cultures of human airway epithelial cells, we undertook a comprehensive examination of factors that enhance eosinophil survival or apoptosis. Unstimulated epithelial cells were compared to epithelial cells stimulated with TNF-alpha in the presence or absence of dexamethasone. A striking increase in survival was observed when peripheral blood eosinophils were cultured with supernatants derived from unstimulated and TNF-alpha-stimulated epithelial cells. Cultured epithelial cells were examined for transcripts of cytokines shown to enhance eosinophil survival (GM-CSF, IL-3, IL-5, IL-13, and IFN-gamma), and transcripts for cytokines promoting apoptosis (IL-10 and TGF-beta). GM-CSF transcripts, but not the other cytokines, were present in unstimulated epithelial cells, and levels were increased with TNF-alpha stimulation. TNF-alpha stimulation increased the levels of GM-CSF and PGE2 in epithelial cell supernatants and dexamethasone suppressed the TNF-alpha induced increases. The survival effects of the TNF-alpha-stimulated supernatants were effectively blocked by neutralizing antibodies to GM-CSF or by dexamethasone treatment of epithelial cells. Selectivity of GM-CSF for eosinophil versus neutrophil survival was demonstrated and suggests that epithelial cell regulation of GM-CSF and PGE2 contribute to eosinophil survival in vitro and may contribute to eosinophil accumulation in allergic disease.
Daffern
P J
PJ
Jagels
M A
MA
Saad
J J
JJ
Fischer
W
W
Hugli
T E
TE
D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D006801:Humans; D012016:Reference Values; D012137:Respiratory System / Q000166:cytology / Q000276:immunology*; D012680:Sensitivity and Specificity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
D005938:Glucocorticoids; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D015232:Dinoprostone