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Infect Immun, June 1998, p. 2562-2569, Vol. 66, No. 6
Department of Microbiology and Immunology,
Uniformed Services University of the Health Sciences, Bethesda,
Maryland 20814-47991;
William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin
537052;
Eisai Research Institute,
Andover, Massachusetts 018103; and
Novartis Forschungsinstitut, A-1235 Vienna,
Austria4
Received 3 November 1997/Returned for modification 6 January
1998/Accepted 13 March 1998
Monocytes/macrophages play a central role in mediating the effects
of lipopolysaccharide (LPS) derived from gram-negative bacteria by the
production of proinflammatory mediators. Recently, it was shown that
the expression of cytokine genes for tumor necrosis factor alpha
(TNF-
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Lipopolysaccharide and Its Analog Antagonists Display
Differential Serum Factor Dependencies for Induction of Cytokine
Genes in Murine Macrophages
), interleukin-1
(IL-1), and interferon-inducible protein-10 (IP-10) by murine macrophages in response to low
concentrations of LPS is entirely CD14 dependent. In this report, we
show that murine macrophages respond to low concentrations of LPS (
2
ng/ml) in the complete absence of serum, leading to the induction of TNF- and IL-1 genes. In contrast to the TNF- and IL-1
genes, the IP-10 gene is poorly induced in the absence of serum. The addition of recombinant human soluble CD14 (rsCD14) had very little effect on the levels of serum-free, LPS-induced TNF-, IL-1, and
IP-10 genes. In contrast, the addition of recombinant human LPS-binding
protein (rLBP) had opposing effects on the LPS-induced TNF- or
IL-1 and IP-10 genes. rLBP inhibited LPS-induced TNF- and IL-1
genes, while it reconstituted IP-10 gene expression to levels induced
in the presence of serum. These results provide further evidence that
the induction of TNF- or IL-1 genes occurs via a pathway that is
distinct from one that leads to the induction of the IP-10 gene and
that the pathways diverge at the level of the initial interaction
between LPS and cellular CD14. Additionally, the results presented here
indicate that LPS structural analog antagonists Rhodobacter
sphaeroides diphosphoryl lipid A and SDZ 880.431 are able to
inhibit LPS-induced TNF- and IL-1 in the absence of serum, while
a synthetic analog of Rhodobacter capsulatus lipid A (B
975) requires both rsCD14 and rLBP to function as an inhibitor.
*
Corresponding author. Mailing address: Department of
Microbiology and Immunology, Uniformed Services University of the
Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814-4799. Phone: (301) 295-3446. Fax: (301) 295-1545. E-mail:
vogel{at}usuhsb.usuhs.mil.
Infect Immun, June 1998, p. 2562-2569, Vol. 66, No. 6
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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