RELEASE OF INTERLEUKIN-8, INTERLEUKIN-6, AND COLONY-STIMULATING FACTORS BY UPPER AIRWAY EPITHELIAL-CELLS - IMPLICATIONS FOR CYSTIC-FIBROSIS

Cystic fibrosis (CF) is characterized by a dramatic neutrophil recruit ment and repeated Pseudomonas infections in the lungs. To evaluate cyt okine releasability by airway epithelial cells in the context of CF, w e studied primary nasal epithelial cells isolated from the upper airwa ys and continuous epithelial cell lines from normal and CF subjects. R elatively low levels of interleukin (IL)-8, IL-6, and granulocyte/macr ophage colony-stimulating factor (GM-CSF) were produced spontaneously by primary epithelial cells (< 50 pg/10(6) cells) and higher levels of colony-stimulating factor-1 (CSF-1) (1 to 2 ng/10(6) cells). Cells we re stimulated with substances that are likely to be present in the inf lamed lungs of CF patients - namely, the proinflammatory monokines IL- 1 and tumor necrosis factor-alpha (TNFalpha) as well as neutrophil ela stase and bacterial products from Pseudomonas (mucoid exopolysaccharid e [MEP] and rhamnolipids). Both IL-1 and TNFalpha induced a dose-depen dent release of IL-6 (5 to 10 ng/10(6) cells) and GM-CSF (2 to 3 ng/10 (6) cells) by primary epithelial cells from eight normal volunteers. T he TNFalpha/IL-1-stimulated GM-CSF release was blocked by the addition of 1 muM dexamethasone, whereas basal CSF-1 release was unaffected. N eutrophil elastase.was a potent inducer of IL-8 and GM-CSF both in pri mary epithelial cells and in cell lines. Dexamethasone (1 muM) did not inhibit elastase-induced IL-8 release in either normal or CF epitheli al cells. Rhamnolipids and MEP were found to stimulate the copious rel ease of IL-8, GM-CSF, and IL-6 from epithelial cells, in a steroid-sen sitive fashion. Epithelial cell lines from normal and CF subjects secr eted very similar amounts of cytokines upon exposure to the various st imuli. We conclude from the above that: (1) proinflammatory cytokine r elease by epithelial cells is induced with leukocyte products and Pseu domonas bacterial products; (2) elastase induces IL-8 release in a man ner unaffected by steroid treatment; (3) CSF-1 release occurs constitu tively, and its spontaneous release may be related to a maintenance fu nction for this cytokine; and (4) continuous epithelial cell lines obt ained from CF subjects do not have an aberrant cytokine secretion prof ile. These results have implications in CF, where high levels of elast ase, monokines, Pseudomonas rhamnolipids, and MEP are generated in the inflamed lungs of CF patients.