Cellular mechanisms that cause suppressed gamma interferon secretion in endotoxin-tolerant mice

T. K. Varma, Tracy Toliver-Kinsky, C. Y. Lin, Aristides Koutrouvelis, Joan Nichols, E. R. Sherwood

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Endotoxin (lipopolysaccharide [LPS]) tolerance is a state of altered immunity characterized, in part, by suppression of LPS-induced gamma interferon (IFN-γ) expression. However, the cellular mediators regulating LPS-induced production of IFN-γ in normal mice and the effect of LPS tolerance on these mediators has not been well characterized. Our studies show that macrophage dysfunction is the primary factor causing suppressed IFN-γ expression in LPS-tolerant mice. Specifically, LPS-tolerant macrophages have a markedly impaired ability to induce IFN-γ secretion by T cells and NK cells obtained from either control or LPS-tolerant mice. However, T cells and NK cells isolated from LPS-tolerant mice produce normal levels of IFN-γ when cocultured with control macrophages or exogenous IFN-γ-inducing factors. Assessment of important IFN-γ-regulating factors showed that interleukin-12 (IL-12) and costimulatory signals provided by IL-15, IL-18, and CD86 are largely responsible for LPS-induced IFN-γ expression in control mice. IL-10 is an inhibitor of IFN-γ production in both the control and LPS-tolerant groups. Expression of IL-12 and the IL-12 receptor β1 (IL-12Rβ1) and IL-12Rβ2 subunits are suppressed in the spleens of LPS-tolerant mice. LPS-tolerant splenocytes also exhibit decreased production of IL-15 and IL-15Rα. However, expression of IL-18 and the B7 proteins CD80 and CD86 are unchanged or increased compared to controls after induction of LPS tolerance. CD28, a major receptor for B7 proteins, is also increased in the spleens of LPS-tolerant mice. Expression of the inhibitory cytokine IL-10 and the IL-10R are sustained after induction of LPS tolerance. These data show that suppression of IFN-γ production in LPS-tolerant mice is largely due to macrophage dysfunction and provide insight into the cellular alterations that occur in LPS tolerance. This study also better defines the factors that mediate LPS-induced IFN-γ production in normal mice.

Original languageEnglish (US)
Pages (from-to)5249-5263
Number of pages15
JournalInfection and Immunity
Volume69
Issue number9
DOIs
StatePublished - 2001

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Endotoxins
Interferon-gamma
Lipopolysaccharides
Macrophages
Interleukin-15
Interleukin-18
Interleukin-12
Natural Killer Cells
Interleukin-10
Interleukin-12 Receptors
Spleen
T-Lymphocytes
Interleukin-1

ASJC Scopus subject areas

  • Immunology

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Cellular mechanisms that cause suppressed gamma interferon secretion in endotoxin-tolerant mice. / Varma, T. K.; Toliver-Kinsky, Tracy; Lin, C. Y.; Koutrouvelis, Aristides; Nichols, Joan; Sherwood, E. R.

In: Infection and Immunity, Vol. 69, No. 9, 2001, p. 5249-5263.

Research output: Contribution to journalArticle

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