This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Harris, H. W. Articles by Kasravi, F. B. Search for Related Content PubMed PubMed Citation Articles by Harris, H. W. Articles by Kasravi, F. B. Social Bookmarking                   What's this?

Lipoprotein-bound LPS induces cytokine tolerance in hepatocytes

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

F. Behzad Kasravi

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

Bacterial endotoxin (LPS) elicits dramatic responses in the host including elevated plasma lipid levels due to the increased synthesis and secretion of triglyceride (TG)-rich lipoproteins by the liver. We postulate that this cytokine-induced hyperlipoproteinemia, clinically termed the `lipemia of sepsis', represents an innate, non-adaptive host immune response to infection. Data in support of this hypothesis include the capacity of TG-rich lipoproteins (VLDL and chylomicrons, CM) to bind and neutralize LPS. Herein, we present evidence that CM-bound LPS attenuates the hepatocellular response to pro-inflammatory cytokines. Primary rodent hepatocytes pretreated with CM—LPS complexes for 2 h demonstrated a near 70% reduction in cytokine-induced NO production as compared to non-pretreated control cells (P 0.04). Whereas hepatocytes were maximally tolerant to cytokine stimulation 6 h after CM—LPS pretreatment, the cells spontaneously regained cytokine responsiveness within 40 h. The induction of cytokine tolerance in hepatocytes follows the internalization of CM—LPS complexes and is a process regulated by the LDL receptor. CM—LPS complexes failed to induce cytokine tolerance in hepatocytes wherein lipoprotein receptor activity was inhibited with high dose receptor associated protein (30 µg/ml). Similarly, CM-bound LPS did not induce tolerance in hepatocytes from ldlr^—/— mice. Thus, the biochemical or genetic inhibition of LDL receptor activity effectively prevented the CM-mediated induction of the cytokine tolerant phenotype. In conclusion, the lipemia of sepsis likely represents a mechanism by which the host combats sporadic, non-life-threatening episodes of endotoxemia. Also, it may indicate a negative regulatory mechanism for the hepatic response to sepsis, serving to effectively down-regulate the acute phase response. A better understanding of how TG-rich lipoproteins modulate the host response to LPS could yield novel biological insights with important clinical implications, including the development of lipid-based therapies for bacterial infections.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?