Modulatory effect of interleukin-10 on the production of platelet-activating factor aod superoxide anions by human leucocytes

We observed that human monocytes (MO) and polymorphonuclear neutrophils (PMN) stimulated by lipopolysaccharide (LPS) produce platelet-activating factor (PAF) in a pattern characterized by an early and a delayed peak of synthesis. The early peak of PAF synthesis was due to a direct stimulation of these cells through mCD14 receptor as it was inhibited by anti-CD14 monoclonal antibody. The delayed and sustained peak of PAF synthesis was dependent on protein synthesis and cytokine production as shown by the inhibitory effect of cycloheximide on both MO and PMN, and of anti-tumour necrosis factor-alpha (anti-TNF-alpha) and of anti-interleukin-8 (anti-IL-8) neutralizing antibodies on MO and PMN respectively. IL-10 completely prevented this second, cytokine-dependent peak of PAF synthesis. In contrast, IL-10 markedly enhanced the first peak of PAF synthesis both in MO and PMN. Moreover, IL-10 was shown to modulate the production of superoxide anions (O-2(-)) on both MO and PMN. As suggested by previous studies, IL-10 inhibited the delayed production of O-2(-). In the present study, we observed that IL-10 directly stimulated an early production of O-2(-). In addition, IL-10 enhanced the synthesis of O-2(-) by MO and PMN challenged with LPS. The IL-10-induced O-2(-) production was dependent, at least in part, from its effect on PAF synthesis, as it was inhibited by the PAF receptor antagonist WEB 2170. These results suggest that IL-10 may upregulate the early synthesis of PAF and O-2(-) triggered by direct LPS stimulation, whereas it may downregulate the delayed production of these mediators.