Platelet-activating factor enhances interleukin-6 production by alveolar macrophages

The production of the cytokine interleukin-6 (IL-6) by rat alveolar macrophages (AMs) was analyzed after their stimulation with muramyl dipeptide (1 microgram/ml), in the presence of graded concentrations of platelet-activating factor (PAF). Significantly enhanced production of IL-6 was observed at 10(-10) to 10(-8) mol/L PAF, with peak effect at 10(-10) mol/L. This enhancement was blocked by three structurally unrelated specific PAF receptor antagonists BN 52021, WEB 2170, and CV 3988. The biologically inactive PAF precursor/metabolite, lyso-PAF, and the enantiomer enantio-PAF failed to induce significant enhancement in IL-6 production. In parallel, addition of PAF to AM triggered leukotriene B4 (LTB4) release. Inhibition of 5-lipoxygenase pathway by AA-861 or MK 886 inhibited the PAF-induced augmentation of both IL-6 and LTB4 production, suggesting an implication of endogenous leukotrienes in this mechanism. Furthermore, addition of exogenous LTB4 to AMs could augment their IL-6 production, with peak activity at 10(-12) mol/L LTB4, and reverse the inhibitory effects of 5-lipoxygenase inhibitors. Taken together, these observations suggest that PAF can modulate lung immune and inflammatory responses by enhancing IL-6 production and that this activity may be dependent on secondary 5-lipoxygenase metabolites. This may have clinical relevance in PAF-mediated events in the lung, such as the cellular components of late-phase asthma.