MURINE MACROPHAGES SECRETE INTERFERON-GAMMA UPON COMBINED STIMULATIONWITH INTERLEUKIN (IL)-12 AND IL-18 - A NOVEL PATHWAY OF AUTOCRINE MACROPHAGE ACTIVATION

Interferon (IFN)-gamma, a key immunoregulatory cytokine, has been thou ght to be produced solely by activated T cells and natural killer cell s. In this study, we show that murine bone marrow-derived macrophages (BMM Phi) secrete large amounts of IFN-gamma upon appropriate stimulat ion. Although interleukin (IL)-12 and IL-18 alone induce low levels of IFN-gamma mRNA transcripts, the combined stimulation of BMM Phi with both cytokines leads to the efficient production of IFN-gamma protein. The macrophage-derived IFN-gamma is biologically active as shown by i nduction of inducible nitric oxide synthase as well as upregulation of CD40 in macrophages. Our findings uncover a novel pathway of autocrin e macrophage activation by demonstrating that the mac macrophage is no t only a key cell type responding to IFN-gamma but also a potent IFN-g amma-producing cell.