title: Lipoprotein-bound LPS induces cytokine tolerance in hepatocytes.
abstract: 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 > or = 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 microg/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.
authors.affiliation: UCSF Surgery Research Laboratory at San Francisco General Hospital, University of California, 94110, USA. harrish@surgery.ucsf.edu
authors.forename: Hobart W
authors.initials: HW
authors.lastname: Harris
authors.forename: F Behzad
authors.initials: FB
authors.lastname: Kasravi
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D002914:Chylomicrons / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004361:Drug Tolerance; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D002914:Chylomicrons; D016207:Cytokines; D004338:Drug Combinations; D026563:LDL-Receptor Related Protein-Associated Protein; D008070:Lipopolysaccharides; D011973:Receptors, LDL; D009569:Nitric Oxide