Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: A novel pathway of autocrine macrophage activation

J Exp Med. 1998 Jun 15;187(12):2103-8. doi: 10.1084/jem.187.12.2103.


Interferon (IFN)-gamma, a key immunoregulatory cytokine, has been thought to be produced solely by activated T cells and natural killer cells. In this study, we show that murine bone marrow- derived macrophages (BMMPhi) secrete large amounts of IFN-gamma upon appropriate stimulation. Although interleukin (IL)-12 and IL-18 alone induce low levels of IFN-gamma mRNA transcripts, the combined stimulation of BMMPhi with both cytokines leads to the efficient production of IFN-gamma protein. The macrophage-derived IFN-gamma is biologically active as shown by induction of inducible nitric oxide synthase as well as upregulation of CD40 in macrophages. Our findings uncover a novel pathway of autocrine macrophage activation by demonstrating that the macrophage is not only a key cell type responding to IFN-gamma but also a potent IFN-gamma-producing cell.

MeSH terms

  • Animals
  • Autocrine Communication*
  • Bone Marrow Cells / drug effects
  • Cytokines / pharmacology*
  • Drug Synergism
  • Feedback
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism*
  • Interleukin-12 / pharmacology*
  • Interleukin-18
  • Macrophage Activation*
  • Macrophages / drug effects
  • Mice
  • Mice, Inbred AKR
  • Mice, Inbred C57BL
  • RNA, Messenger / biosynthesis


  • Cytokines
  • Interleukin-18
  • RNA, Messenger
  • Interleukin-12
  • Interferon-gamma