Lipoprotein-bound LPS induces cytokine tolerance in hepatocytes
| Autor: | Hobart W. Harris, F. Behzad Kasravi |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Lipopolysaccharides
Male 0301 basic medicine Very low-density lipoprotein medicine.medical_treatment 030106 microbiology Immunology Pharmacology Nitric Oxide Transfection Microbiology Adenoviridae LDL-receptor-related protein-associated protein Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Chylomicrons medicine Animals Humans LDL-Receptor Related Protein-Associated Protein Receptor Molecular Biology Cells Cultured Mice Knockout Dose-Response Relationship Drug biology Acute-phase protein Drug Tolerance Cell Biology Rats Drug Combinations Cytokine Infectious Diseases Receptors LDL LDL receptor Hepatocytes biology.protein Cytokines lipids (amino acids peptides and proteins) 030215 immunology Chylomicron Lipoprotein |
| Zdroj: | Journal of Endotoxin Research. 9:45-50 |
| ISSN: | 0968-0519 |
| DOI: | 10.1179/096805103125001333 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|