INTERLEUKIN-10 AND INTERLEUKIN-4 INHIBIT INTRACELLULAR KILLING OF LEISHMANIA-INFANTUM AND LEISHMANIA-MAJOR BY HUMAN MACROPHAGES BY DECREASING NITRIC-OXIDE GENERATION

The host response to Leishmania infection is regulated by a specific p attern of local cytokine production. We investigated the effect of int erleukin (IL)-10 and IL-4 on the leishmanicidal activity of human macr ophages (M phi). As with L. major, intracellular killing of L. infantu m by human M phi was obtained following ligation of surface CD23 or ce ll treatment with interferon-gamma (IFN-gamma). This leishmanicidal ac tivity required nitric oxide (NO) generation by activated M phi, and i t was partially mimicked by cell treatment with chemical NO donors. Ad dition of recombinant human IL-10 or IL-4 to CD23 mAB or IFN-gamma dec reased L. infantum and L. major killing by infected M phi. IL-10 was m ore potent than IL-4 in inhibiting the leishmanicidal activity of huma n M phi. Inhibition of Leishmania killing by IL-4 and IL-10 correlated with decreased NO generation from M phi, and was reversed when exogen ous No was added to cell cultures. Therefore, IL-10 and IL-4 down-regu late leishmanicidal activity of human M phi, in part by inhibiting NO generation by these cells.