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© The Rockefeller University Press, 0022-1007/1997/3/921/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 5, March 3, 1997 921-932

Articles

Crucial Role of Interferon Consensus Sequence Binding Protein, but neither of Interferon Regulatory Factor 1 nor of Nitric Oxide Synthesis for Protection Against Murine Listeriosis

Thomas Fehr*, Gabriele Schoedon{ddagger}, Bernhard Odermatt§, Thomas Holtschke||, Markus Schneemann{ddagger}, Martin F. Bachmann*,¶, Tak W. Mak, Ivan Horak||, and Rolf M. Zinkernagel*

From the * Institute of Experimental Immunology, University Hospital, CH-8091 Zürich, Switzerland; {ddagger} Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland; § Department of Pathology, University Hospital, CH-8091 Zürich, Switzerland; || Department of Molecular Genetics, Research Institute of Molecular Pharmacology, D-12207 Berlin, Germany; and Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, M4X1K9, Canada

Listeria monocytogenes is widely used as a model to study immune responses against intracellular bacteria. It has been shown that neutrophils and macrophages play an important role to restrict bacterial replication in the early phase of primary infection in mice, and that the cytokines interferon-{gamma} (IFN-{gamma}) and tumor necrosis factor-{alpha} (TNF-{alpha}) are essential for protection. However, the involved signaling pathways and effector mechanisms are still poorly understood. This study investigated mouse strains deficient for the IFN-dependent transcription factors interferon consensus sequence binding protein (ICSBP), interferon regulatory factor (IRF)1 or 2 for their capacity to eliminate Listeria in vivo and in vitro and for production of inducible reactive nitrogen intermediates (RNI) or reactive oxygen intermediates (ROI) in macrophages. ICSBP–/– and to a lesser degree also IRF2–/– mice were highly susceptible to Listeria infection. This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-{gamma} in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-{gamma} stimulation, whereas nitric oxide production was normal. In contrast, mice deficient for IRF1 were not able to produce nitric oxide, but they efficiently controlled Listeria in vivo and in vitro. These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-{gamma}–mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.

Address correspondence to Thomas Fehr, Institute of Experimental Immunology, University Hospital, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.

1Abbreviations used in this paper: ICSBP, interferon consensus sequence binding protein; i.f., into the footpad; iNOS, inducible nitric oxide synthase; IRF1/2, interferon regulatory factor 1/2; ISGF, interferon-stimulated gene factor; ISRE, interferon-stimulated response element; NO, nitric oxide; PEM, peritoneal macrophage; RNI, reactive nitrogen intermediates; ROI, reactive oxygen intermediates; STAT, signal transducers and activators of transcription.


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