Interleukin-8 (IL-8) is a proinflammatory peptide secreted by activated endothelial cells. Vascular injury frequently results from excessive IL-8 secretion during spesis, trauma, or ischemia-reperfusion injury. Nitric oxide (NO), which has many important physiological roles, can serve an anti-inflammatory role under conditions of intense endothelial activation but may be proinflammatory under other conditions and promote IL-8 secretion. Research performed by the applicant suggests that NO may have different regulatory actions on IL-8 gene expression depending on the activation state of the endothelium.
The aims of the proposal are (1) to characterize the role of NO in stimulus-specific regulation of IL-8 expression in activated in vitro endothelium; (2) to define promoter regions of the IL-8 gene necessary for IL-8 induction in resting endothelium; (3) to identify transcription factors involved in mediating NO's effects on endothelial IL-8 expression; and (4) to use site-directed mutagenesis to confirm identity and activity of transcription factors conferring NO-responsiveness in promoter constructs. A number of different molecular techniques will be used to accomplish these aims. There is still an incomplete understanding of NO's regulation of inflammation, yet human trials of NO therapy for inflammatory injury of the lung are under way. A great deal remains to be learned about NO's role in the inflammatory process.
