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Infection and Immunity, January 1999, p. 206-212, Vol. 67, No. 1
Abteilung für Innere Medizin m.S.
Hämatologie und Onkologie, Virchow-Klinikum der
Humboldt-Universität, 13357 Berlin,
Germany,1 and
Division of Infectious
Diseases,
Received 20 January 1998/Returned for modification 10 April
1998/Accepted 17 September 1998
When given in the presence of gamma interferon (IFN-
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
), 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-
B and IFN-
-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-
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-
, IFN-
strongly augmented LPS-induced NF-
B activation and
accelerated the binding of NF-
B to DNA to as early as 5 min. In
agreement with this, IFN-
pretreatment promoted rapid degradation of
I
B-
but not that of I
B-
. Inhibition of protein synthesis during IFN-
treatment suppressed LPS-initiated NF-
B binding. A
rapidly induced protein appeared to be involved in IFN-
priming. Preincubation of cells with antibodies to tumor necrosis factor alpha
or the interleukin-1 receptor partially reduced the priming effect of
IFN-
. In a complementary manner, LPS enhanced the activation of
signal-transducing activator of transcription 1 by IFN-
. These data
suggest novel mechanisms for the synergy between IFN-
and LPS by
which they cross-regulate the signal-transducing molecules. Through
this mechanism, IFN-
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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