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

UCSF Surgical Research Laboratory at San Francisco General Hospital, University of California, San Francisco, California, USA

Diana H. Lee

UCSF Surgical Research Laboratory at San Francisco General Hospital, University of California, San Francisco, California, USA

Karl Weisgraber

Gladstone Institute for Cardiovascular Diseases, University of California, San Francisco, California, USA

Hobart W. Harris

UCSF Surgical Research Laboratory at San Francisco General Hospital, University of California, San Francisco, California, USA, harrish{at}surgery.ucsf.edu

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Key Words: Lipoproteins • LPS • cytokine tolerance • rat • sepsis

Journal of Endotoxin Research, Vol. 11, No. 1, 19-24 (2005)
DOI: 10.1177/09680519050110010601


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