Lipoprotein-bound endotoxin exerts an immunomodulatory effect on hepatocytes through the lipid A domain of LPS

We have previously shown that chylomicron (CM)-bound lipopolysaccharide (LPS) inhibits the host innate immune response by rendering hepatocytes tolerant to pro-inflammatory cytokine stimulation. However, LPS is a complex macromolecule containing both lipid and carbohydrate domains. We hypothesized t...

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Bibliographic Details
Published in:Journal of endotoxin research 2005-01, Vol.11 (1), p.19-24
Main Authors: Kasravi, F Behzad, Lee, Diana H, Weisgraber, Karl, Harris, Hobart W
Format: Article
Language:English
Subjects:
Animals
Cell Culture Techniques
Cells, Cultured
Chylomicrons - metabolism
Cytokines - metabolism
Endotoxins - pharmacology
Hepatocytes - drug effects
Hepatocytes - metabolism
Lipid A - chemistry
Lipopolysaccharides - chemistry
Lipopolysaccharides - metabolism
Lipopolysaccharides - pharmacology
Macrophages - drug effects
Macrophages - enzymology
Male
Nitric Oxide - biosynthesis
Protein Structure, Tertiary
Rats
Rats, Sprague-Dawley
Time Factors
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Summary:We have previously shown that chylomicron (CM)-bound lipopolysaccharide (LPS) inhibits the host innate immune response by rendering hepatocytes tolerant to pro-inflammatory cytokine stimulation. However, LPS is a complex macromolecule containing both lipid and carbohydrate domains. We hypothesized that just as lipid A confers the toxicity of LPS, it is also responsible for the immunoregulatory effect on hepatocytes. We pretreated primary rat hepatocytes for 2 h with a series of CM-LPS complexes in which the endotoxin moiety varied in its structure and/or toxicity. Subsequently, the cells were stimulated with a mixture of pro-inflammatory cytokines. Nitric oxide production was measured as an indicator of hepatocellular activation. All pretreatments wherein the CM-bound complex contained the lipid A moiety readily inhibited the hepatocellular cytokine response, including CM bound to lipid A alone. In contrast, CM-LPS complexes containing detoxified LPS, which lacks the lipid A domain, had no effect on the hepatocellular response to cytokines. The lipid A domain of the LPS macromolecule is both sufficient and essential for the CM-mediated induction of cytokine tolerance in hepatocytes. However, this process is independent of the specific endotoxic activity of the lipid A moiety.
ISSN:0968-0519
1743-2839
DOI:10.1179/096805105225006731