Redox-dependent regulation of interleukin-1 by tumor necrosis factor-alphain lung epithelial cells

Increasing evidence supports a major role for progression of inflammatory l ung diseases. The present studies were designed to characterize the molecul ar events involved in IL-8 induction in pulmonary epithelial cells in respo nse to tumor necrosis factor-alpha (TNF-alpha). IL-8 induction by TNF-alpha was redox sensitive, as indicated by electron spin resonance analysis and inhibition with membrane permeable hydroxyl scavengers. Furthermore using c ell transfection and mobility shift assays, ii was found that transcription al activation of the IL-8 gene required TNF-alpha-induced activation and bi nding of nuclear factor-kappa B (NF-kappa B)- and NF-IL-6, nuclear transcri ption factors to regulatory elements in the IL-8 promoter. Activation of th e IL-8 promoter by these transcription factors was also redox-sensitive. Th is response was mediated through the TNF-RI receptor (p55), and not the TNF -R2 (p75) receptor, although both receptors can be found on pulmonary epith elial cells. Taken together these studies indicate that TNF-alpha-induced r edox changes in lung epithelial cells are responsible for the transcription al activation of IL-8 and that coordinate activation of NF-kappa B and NF-I L-6 mediate the response.