Dysregulated cytokine production in human cystic fibrosis bronchial epithelial cells

Although pulmonary inflammation is an important pathologic event in cystic fibrosis (CF), the relationship between expression of the CF gene and the i nflammatory response is unclear. We studied tumor necrosis factor (TNF) alp ha and IL-1 beta stimulated production of IL-6 and IL-8 by CF, corrected CF , and normal human bronchial epithelial cells in culture. During the first 24 hours of TNF alpha stimulation, CF cells produced significantly more IL- 8 than normal or corrected CF cells. In the second 24 hours of TNF alpha st imulation, IL-6 and IL-8 generation ceased in normal and corrected CF cells but accelerated in CF cells, resulting in marked IL-6 and IL-8 accumulatio n in CF cells. Similar results were found when cells were stimulated with I L-1 beta. Finally, when CF cells were grown at 27 degreesC (a culture condi tion which results in transport of CF transmembrane conductance regulator, CFTR, to the cell membrane and normalization of chloride conductance) TNF d egrees -stimulated production of IL-6 and IL-8 reverted to normal. We concl ude that dysregulation of cytokine generation by CF bronchial epithelial ce lls is directly related to expression of mutant CFTR and these observations provide a potential mechanism for persistence of airway inflammation in CF .