IL-10 UP-REGULATES HUMAN MONOCYTE PHAGOCYTOSIS IN THE PRESENCE OF IL-4 AND IFN-GAMMA

Interleukin-10 (IL-10), a cytokine produced by type 2 helper T (Th2) c ells, inhibits the microbicidal effector function of interferon-gamma (IFN-gamma)-activated macrophages. However, recent observations indica te that IL-10 like IFN-gamma, increases Fc gamma RI expression and Fc gamma R-mediated cytotoxic activity on human monocytes, suggesting tha t this cytokine cannot be classified purely as a monocyte deactivator. The present study found that incubation for 40 h of human monocytes o r monocyte derived macro phages in the presence of IL-10 caused a sign ificant enhancement of their capacity to ingest particles coated with immunoglobulin G (Fc gamma R-mediated ingestion) or with C3b/C3bi frag ments of the complement system (CR1/CR3-mediated ingestion). The numbe r of phagocytosing cells (% phagocytosis) and the number of ingested p articles per cell (phagocytic index) were both significantly higher af ter 40-h incubation of monocytes with IL-10 concentrations greater tha n or equal to 1 U/ml. This up regulating activity on phagocytosis was completely reversed by anti-IL-10 monoclonal antibody (mAb), As previo usly reported, IG 10 stimulated Fc gamma RI expression on monocytes bu t did not induce the expression of Fc gamma RII, Fc gamma RIII, CR1, a nd CR3, IFN-gamma, like IL-10, up-regulated only Fc gamma RI expressio n but significantly reduced both Fc gamma R- and CR-mediated ingestion , IL-10 almost completely reversed the IFN-gamma-induced inhibition of both Fc gamma R- and CR-mediated phagocytosis, without concomitant ch anges in membrane expression of phagocytic receptors. Exposure of mono cytes to IL-4 reduced the membrane expression of all three Fc gamma Rs and also inhibited Fc gamma R-mediated ingestion, On the other hand, IL-4 up-regulated both CR3 expression and CR-mediated ingestion on cul tured monocytes, IL-10 not only neutralized the down-regulatory effect of IL-4 on Fc gamma R expression but also completely reversed the IL- 4-induced suppression of Fc gamma R-mediated phap ocytosis. Fxpo sure of monocytes to a combination of IL-10 and IL-4 resulted in a synergis tic effect on CR-mediated ingestion, even though no additive effects w ere observed on CR membrane expression, Finally, culture of monocytes in medium containing anti-IL-10 mAb significantly reduced their capaci ty to ingest IgG- or C3b/C3bi-coated particles, suggesting a role for endogenously produced II,10 in the modulation of phagocytosis by human monocytes. These results demonstrate that IL-10 is a potent up-regula tor of the phagocytic activity of human mononuclear phagocytes and ind icate that this function may be in sensitive balance with the relative concentrations of IL-10, IL-4, and IFN-gamma.