J. Exp. Med., Volume 187, Number 12, June 15, 1998 2103-2108

Murine Macrophages Secrete Interferon  upon Combined Stimulation with Interleukin (IL)-12 and IL-18: A Novel Pathway of Autocrine Macrophage Activation

By Markus Munder, Moisés Mallo, Klaus Eichmann, and Manuel Modolell

From the Max-Planck-Institut für Immunbiologie, D-79108 Freiburg, Germany

Interferon (IFN)-, 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 (BMM) secrete large amounts of IFN- upon appropriate stimulation. Although interleukin (IL)-12 and IL-18 alone induce low levels of IFN- mRNA transcripts, the combined stimulation of BMM with both cytokines leads to the efficient production of IFN- protein. The macrophage-derived IFN- 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- but also a potent IFN--producing cell.

macrophage;  interferon ;  interleukin 12;  interleukin 18;  innate immunity

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• Matsunaga, K., Klein, T. W., Friedman, H., Yamamoto, Y. (2001). Legionella pneumophila Replication in Macrophages Inhibited by Selective Immunomodulatory Effects on Cytokine Formation by Epigallocatechin Gallate, a Major Form of Tea Catechins. Infect. Immun. 69: 3947-3953 [Abstract] [Full Text]  
• Remer, K. A., Jungi, T. W., Fatzer, R., Tauber, M. G., Leib, S. L. (2001). Nitric Oxide Is Protective in Listeric Meningoencephalitis of Rats. Infect. Immun. 69: 4086-4093 [Abstract] [Full Text]  
• Horwood, N. J., Elliott, J., Martin, T. J., Gillespie, M. T. (2001). IL-12 Alone and in Synergy with IL-18 Inhibits Osteoclast Formation In Vitro. J. Immunol. 166: 4915-4921 [Abstract] [Full Text]  
• Fukao, T., Frucht, D. M., Yap, G., Gadina, M., O'Shea, J. J., Koyasu, S. (2001). Inducible Expression of Stat4 in Dendritic Cells and Macrophages and Its Critical Role in Innate and Adaptive Immune Responses. J. Immunol. 166: 4446-4455 [Abstract] [Full Text]  
• Schindler, H., Lutz, M. B., Rollinghoff, M., Bogdan, C. (2001). The Production of IFN-{{gamma}} by IL-12/IL-18-Activated Macrophages Requires STAT4 Signaling and Is Inhibited by IL-4. J. Immunol. 166: 3075-3082 [Abstract] [Full Text]  
• Merlin, T., Sing, A., Nielsen, P. J., Galanos, C., Freudenberg, M. A. (2001). Inherited IL-12 Unresponsiveness Contributes to the High LPS Resistance of the Lpsd C57BL/10ScCr Mouse. J. Immunol. 166: 566-573 [Abstract] [Full Text]  
• Cai, G., Kastelein, R., Hunter, C. A. (2000). Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii. Infect. Immun. 68: 6932-6938 [Abstract] [Full Text]  

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