Multiple epithelial cell-derived factors enhance neutrophil survival - Regulation by glucocorticoids and tumor necrosis factor-alpha

We examined the potential of several epithelial-derived factors to enhance neutrophil activation and survival. Neutrophils incubated in the presence o f supernatants from nasal-derived primary epithelial cultures had significa ntly increased survival compared with neutrophils cultured in media alone. Of the cytokines reported to enhance neutrophil survival, transcripts for i nterleukin (LL)-1 alpha, 1L-1 beta, IL-6, and granulocyte macrophage colony -stimulating factor (GM-CSF) (but not interferon-gamma or granulocyte colon y-stimulating factor [G-CSF]) were detected by ribonuclease protection assa y in basal and tumor necrosis factor (TNF)-alpha-stimulated epithelial cell s. Of the eicosanoid products that enhance neutrophil survival, platelet-ac tivating factor and leukotriene B-4 were not detected in the supernatants, whereas prostaglandin E-2 (PGE(2)) was produced in modest amounts. The leve ls of IL-6, GM-CSF, and PGE2 in epithelial supernatants were significantly increased after transient TNF-alpha stimulation, This induction was suppres sed if dexamethasone (Dex) was added during TNF-alpha stimulation. Only IL- 6, GM-CSF, and PGE(2) promoted neutrophil survival over the range of concen trations detected in the supernatants, and a combination of neutralizing an tibodies to GM-CSF and IL-6 completely inhibited the enhanced neutrophil su rvival in epithelial supernatants. Both the terminal deoxynucleotidyl trans ferase-mediated deoxyuridine triphosphate nick-end labeling technique and m orphologic scoring of apoptotic neutrophils confirmed that epithelial super natants, as well as purified IL-6, GM-CSF, and PGE(2) all delayed neutrophi l apoptosis, Finally, the effects of Dex on neutrophil survival and on epit helial cytokine production were investigated. Dex independently prolonged n eutrophil survival but suppressed epithelial production of survival-enhanci ng factors in a dose-dependent manner. The net effect of Dex appeared to fa vor neutrophil survival.