A POSSIBLE NOVEL PATHWAY OF REGULATION BY MURINE T-HELPER TYPE-2 (TH2) CELLS OF A TH1 CELL-ACTIVITY VIA THE MODULATION OF THE INDUCTION OF NITRIC-OXIDE SYNTHASE ON MACROPHAGES

Murine peritoneal macrophages activated with interferon (IFN)-gamma and lipopolysaccharide (LPS) produce high levels of nitric oxide (NO) and are efficient in killing the intracellular protozoan parasites Leishmania major in vitro. Earlier studies have shown that NO, whose synthesis is murine macrophages is catalyzed by an inducible enzyme NO synthase, plays a major effector role in the host resistance against microbial infection. We now show that both the NO synthesis and the leishmanicidal activity can be inhibited by prior treatment of the cells with recombinant interleukin 4 (IL 4). IL 4 treatment had no effect on the binding of IFN-gamma to macrophages but prevented the induction of NO synthase in these cells activated with IFN-gamma and LPS. Since IFN-gamma is produced by murine T helper type-1 (T(h)1) cells, whereas IL 4 is secreted by T(h)2 cells, these results suggest a novel pathway by which T(h)2 cells regulate an activity of T(h)1 cells, namely by inhibiting the induction of NO synthase. These results may also account for the mechanism by which the disease-promoting T(h)2 cells counteract the host-protective effect of T(h)1 cells in leishmaniasis and other intracellular parastic diseases.