Transcriptional activation of the interleukin-8 gene by platelet-activating factor in human peripheral blood...

Interleukin-8 (IL-8) is a member of the chemokine family and a potent neutrophil chemoattractant and activator. It is produced by a variety of cell types during inflammation. In the present work, we examined the regulation of IL-8 gene expression in monocytes by the pro-inflammatory lipid mediator, platelet-activating factor (PAF). Stimulation of human peripheral blood monocytes with PAF augmented their release of IL-8. The enhancement of IL-8 secretion was associated with an increase in IL-8 mRNA expression. PAF induced a concentration- and time-dependent augmentation of IL-8 mRNA accumulation. The response was maximal at PAF concentrations of 10-100 nM. The increased mRNA expression was evident after 1.5 hr of stimulation and persisted for 6 hr. Stimulation of monocytes with PAF, followed by arrest of de novo transcription with actinomycin D, indicated that PAF only marginally increased the stability of IL-8 mRNA. However, in vitro nuclear transcription demonstrated that the enhancement of IL-8 mRNA expression occurred mainly at the transcriptional level. The PAF-induced increase in IL-8 mRNA levels could be blocked with a PAF receptor antagonist. These results show, for the first time, that IL-8 gene expression and protein production can be upregulated by PAF. This interaction could be important in the development and amplification of the inflammatory response.