REGULATION OF CYTOKINE GENE-EXPRESSION BY REACTIVE OXYGEN AND REACTIVE NITROGEN INTERMEDIATES

Reactive oxygen intermediates (ROI), reactive nitrogen intermediates ( RNI), and cytokines are frequent companions at sites of acute inflamma tion. Previous work has established a clear link between the productio n of cytokines and the subsequent generation of ROI and RNI. However, more recent data indicates that ROI and RNI not only serve as end-stag e effector molecules of pathogen destruction and tissue injury, but al so as initiators of acute inflammation. Specifically, ROI and RNI will upregulate cytokine gene expression since antioxidants inhibit interl eukin 8 (IL-8) production and do not decrease production of other cyto kines. Treatment with hydroxyl radical scavengers such as dimethyl sul foxide (DMSO) will decrease the production of IL-8 in stimulated human whole blood, fibroblasts, type II epithelial cells, and hepatoma cell s, but not other cytokines. Addition of exogenous ROI will increase IL -8 production in these same cells, Inhibition of nitric oxide synthase will decrease production of IL-8, whereas addition of nitric oxide (N O)-generating compounds will increase production of IL-8. The hydroxyl radical appears to be the final common pathway of cell activation for IL-8 synthesis, since DMSO will inhibit the NO-driven production of I L-8. Our data indicate that ROI and RNI can serve as intracellular sec ond messengers to induce IL-8 gene expression.