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) cells, inhibits the microbicidal effector function of interferon-gamma (IFN-gamma)-activated macrophages. However, recent observations indicate that IL-10 like IFN-gamma, increases Fc gamma RI expression and Fc gamma R-mediated cytotoxic activity on human monocytes, suggesting that this cytokine cannot be classified purely as a monocyte deactivator. The present study found that incubation for 40 h of human monocytes or monocyte derived macro phages in the presence of IL-10 caused a significant enhancement of their capacity to ingest particles coated with immunoglobulin G (Fc gamma R-mediated ingestion) or with C3b/C3bi fragments of the complement system (CR1/CR3-mediated ingestion). The number of phagocytosing cells (% phagocytosis) and the number of ingested particles per cell (phagocytic index) were both significantly higher after 40-h incubation of monocytes with IL-10 concentrations greater than or equal to 1 U/ml. This up regulating activity on phagocytosis was completely reversed by anti-IL-10 monoclonal antibody (mAb), As previously reported, IG 10 stimulated Fc gamma RI expression on monocytes but did not induce the expression of Fc gamma RII, Fc gamma RIII, CR1, and CR3, IFN-gamma, like IL-10, up-regulated only Fc gamma RI expression 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 changes in membrane expression of phagocytic receptors. Exposure of monocytes 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 cultured 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 synergistic effect on CR-mediated ingestion, even though no additive effects were observed on CR membrane expression, Finally, culture of monocytes in medium containing anti-IL-10 mAb significantly reduced their capacity 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-regulator of the phagocytic activity of human mononuclear phagocytes and indicate that this function may be in sensitive balance with the relative concentrations of IL-10, IL-4, and IFN-gamma.