Platelet-activating factor(PAF) enhances interleukin-1 activity by alveolar macrophages: Modulation by endogenous lipoxygenase and cyclooxygenase metabolites

Abstract

It is becoming increasingly clear that the inflammatory reaction can be ascribed to a complex array of mediators produced from activated phagocytes. The object of this study was to investigate the effect of PAF nn interleukin-1(IL-1) production by rat alveolar macrophages(AM) and the role of endogenous lipoxygenase and cyclooxygenase metabolites in PAF-induccd IL-1 activity. When AM were cultured with PAF alone, no change in IL-1 activity was observed. However, the combined addition of PAF and muramyl dipeptide(MDP) or lipopolysaccharide(LPS) to AM markedly enhanced IL-1 activity by two to three fold over the range of 10 -16 to 10 -8 M PAF compared with AM cultures with MDP or LPS. The peak effect was found at 10 -8 M PAF with MDP and at 10 -14 PAF with LPS. The effect of PAF was also examined in silica, toxic respirable dust, -added AM cultures. PAF(10 -12 M) could enhance IL-1 activitv by two fold above the value of the silica-treated AM. PAF precursor and metabolite, lyso-PAF failed to enhance IL-1 activity in LPS or MDP-stimulated AM. This enhancement was blocked by the specific PAF receptor antagonists, BN 52021 and CV 3988. Furthermore, the 5-lipoxygenase inhibitors such as AA-861 and nordihydroguairetic acid completely blocked PAF-induced enhancement of IL-1, suggesting the involvement of endogenous 5-lipoxygenase activity in the action mechanism of PAF. In contrast, the inhibition of cyclooxygenase pathway by ibuprofen resulted in potentiation of PAF-induced IL-1 activity. These data suggest that PAF enhances IL-1 activity by binding with a specific receptor, and that endogenous 5-lipoxygenase and cyclooxygenase metabolites modulate IL-1 activity induced by PAF.