PLATELET-ACTIVATING-FACTOR EXERTS MITOGENIC ACTIVITY AND STIMULATES EXPRESSION OF INTERLEUKIN-6 AND INTERLEUKIN-8 IN HUMAN LUNG FIBROBLASTSVIA BINDING TO ITS FUNCTIONAL RECEPTOR

Platelet-activating factor (PAF) is a potent proinflammatory phospholi pid mediator of the lung. In this study, we demonstrate that PAF recep tor mRNA and protein is expressed by human lung fibroblasts. Interacti on of PAF with its specific receptor resulted ill increases of tyrosin e phosphorylation of several intracellular proteins, indicating that t ile PAF-receptor might be functionally active. PAF-induced transcripti on of protooncogenes c-fos and c-jun as well as oi interleukin (IL)-6 and IL-8 genes in human fibroblasts. Transcription of the interleukins was followed by secretion of the respective proteins. Moreover, PAF e nhanced proliferation of fibroblasts in a concentration-dependent mann er. Using signaling inhibitors; we demonstrate that PAF-induced transc ription of the c-fos, IL-6, and IL-8 genes, as well as proliferation, require activation of pertussis toxin-sensitive G proteins, tyrosine k inases, and protein kinase C (PKC). In contrast, transcription of c-ju n was blocked by pertussis toxin, but not by inhibitors for tyrosine k inases or PKC. These data suggest that PAF stimulates distinct signali ng pathways in human lung fibroblasts. In addition, the activation of human fibroblasts by PAF leads to enhanced proliferation and to the ex pression of proinflammatory cytokines, which may contribute to dir pat hophysiological changes in pulmonary inflammation.