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Infection and Immunity, January 1999, p. 206-212, Vol. 67, No. 1
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Gamma Interferon Augments Macrophage Activation by Lipopolysaccharide by Two Distinct Mechanisms, at the Signal Transduction Level and via an Autocrine Mechanism Involving Tumor Necrosis Factor Alpha and Interleukin-1

Thomas K. Held,1,2 Xiao Weihua,3 Liang Yuan,2 Dhananjaya V. Kalvakolanu,3,4,5 and Alan S. Cross2,3,*

Abteilung für Innere Medizin m.S. Hämatologie und Onkologie, Virchow-Klinikum der Humboldt-Universität, 13357 Berlin, Germany,1 and Division of Infectious Diseases, Department of Medicine,2 Department of Microbiology & Immunology,4 Molecular and Cellular Biology Program,5 and Greenebaum Cancer Center, Program in Oncology,3 University of Maryland School of Medicine, Baltimore, Maryland 21201

Received 20 January 1998/Returned for modification 10 April 1998/Accepted 17 September 1998

When given in the presence of gamma interferon (IFN-gamma ), otherwise nontoxic doses of lipopolysaccharide (LPS or endotoxin) become highly lethal for mice. The mechanisms of this synergistic toxicity are not known. We considered the possibility that an interaction between the LPS-induced NF-kappa B and IFN-gamma -induced JAK-STAT pathways at the pretranscriptional level may enhance the LPS-induced signals. To test this hypothesis, we incubated murine macrophage RAW 264.7 cells with IFN-gamma for 2 h before addition of different doses of LPS. Consistent with the synergistic induction of inducible nitric oxide synthase mRNA and nitric oxide production by a combination of LPS and IFN-gamma , IFN-gamma strongly augmented LPS-induced NF-kappa B activation and accelerated the binding of NF-kappa B to DNA to as early as 5 min. In agreement with this, IFN-gamma pretreatment promoted rapid degradation of Ikappa B-alpha but not that of Ikappa B-beta . Inhibition of protein synthesis during IFN-gamma treatment suppressed LPS-initiated NF-kappa B binding. A rapidly induced protein appeared to be involved in IFN-gamma priming. Preincubation of cells with antibodies to tumor necrosis factor alpha or the interleukin-1 receptor partially reduced the priming effect of IFN-gamma . In a complementary manner, LPS enhanced the activation of signal-transducing activator of transcription 1 by IFN-gamma . These data suggest novel mechanisms for the synergy between IFN-gamma and LPS by which they cross-regulate the signal-transducing molecules. Through this mechanism, IFN-gamma may transform a given dose of LPS into a lethal stimulus capable of causing sepsis. It may also serve a beneficial purpose by enabling the host to respond quickly to relatively low doses of LPS and thereby activating antibacterial defenses.

* Corresponding author. Mailing address: Greenebaum Cancer Center, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201. Phone: (410) 328-2565. Fax: (410) 328-6896. E-mail: across{at}umcc01.umcc.ab.umd.edu.

Infection and Immunity, January 1999, p. 206-212, Vol. 67, No. 1
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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Copyright © 1999 by the American Society for Microbiology. All rights reserved.