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.