Hepatic cytochromes P-450 (CYP) are well characterized drug and xenobiotic metabolizing enzymes that are extensively regulated by genetic and environmental factors. Inflammatory mediators, including interleukins (ILs), interferons (IFNs), and tumor necrosis factor-α (TNF-α), have been shown to down-regulate several CYP isoforms; however, elucidation of the inflammatory mediators that are responsible for specific CYP down-regulation is difficult. The purpose of this experiment was to evaluate the role endogenous TNF-α plays in the regulation of liver CYP expression after endotoxin administration. Mice deficient in the p55 and p75 TNF receptors and wild-type mice were given Gram-negative bacterial lipopolysaccharide (LPS) and killed 24 h after administration. CYP analysis indicates that LPS decreases CYP1A, CYP2B, CYP3A, and CYP4A independently of TNF-α. CYP2D9 and CYP2E1 activities show differential responses to LPS between wild-type and TNF p55/p75 receptor knockout mice, indicating the down-regulation of CYP2D9 and CYP2E1 is differentially modulated by TNF-α expression. Furthermore, TNF-α appears to affect the constitutive expression of CYP2D9 and CYP2E1. To date, this is the first evidence suggesting that a proinflammatory cytokine is involved in the constitutive regulation of drug-metabolizing enzymes.

Hepatic Cytochrome P-450 Expression in Tumor Necrosis Factor-α Receptor (p55/p75) Knockout Mice After Endotoxin Administration

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840200621

Induction of hepatic ito cell nitric oxide production after acute endotoxemia

Much evidence indicates that bacterial LPS (endotoxin) is removed from the bloodstream mainly by the liver, yet the hepatic uptake mechanisms remain uncertain and controversial. In plasma, LPS can be either 'free' (as aggregates, bacterial membrane fragments or loosely bound to albumin, CD14, or other proteins) or 'bound' (complexed with lipoproteins). Whereas most free LPS is taken up by Kupffer cells (KCs), lipoprotein-bound LPS has seemed to be cleared principally by hepatocytes. Here, we compared the liver's ability to take up and deacylate free LPS aggregates and the LPS in preformed LPS-high density lipoprotein (HDL) complexes. In mice examined from 1 h to 7 d after a small amount of fluorescent (FITC-)LPS was injected into a lateral tail vein, we found FITC-LPS almost entirely within, or adjacent to, KCs. As expected, FITC-LPS complexed with HDL (FITC-LPS-HDL) disappeared more slowly from the circulation and a smaller fraction of the injected dose of FITC-LPS was found in the liver. Unexpectedly, the FITC-LPS injected as FITC-LPS-HDL complexes was also found within sinusoids, adjacent to, or within, KCs. In other experiments, we found that both free and HDL-bound radiolabeled LPS underwent enzymatic deacylation by acyloxyacyl hydrolase (AOAH), the LPS-inactivating enzyme that is principally produced within the liver by KCs. Our observations suggest that KCs and AOAH play important roles in clearing and catabolizing both free LPS and the LPS in circulating LPS-HDL complexes.

/pdf/hepatic-uptake-and-deacylation-of-the-lps-in-bloodborne-lps-3klr6q6w7x.pdf

Hepatic uptake and deacylation of the LPS in bloodborne LPS-lipoprotein complexes.

Dendritic cell (DC), macrophage (Mphi) and lymphocyte infiltrations have been observed in normal human perinatal pancreata, but have never been investigated so early in control mice. In type 1 diabetes-prone NOD mice, these cells are thought to infiltrate first the periphery of the islets of Langerhans around weaning before further islet infiltration and beta-cell destruction. We quantified, during the first month of life, the numbers of DC (characterized by CD11c positivity and dendritic morphology), histiocyte-like Mphi (characterized by ER-MP23 positivity) and Mphi with scavenging potential (characterized by BM8 positivity) in C57BL/6, DBA/2 and BALB/c control, and NOD and lymphocyte-deficient NODscid mouse pancreata. First, CD11c+ DC were present at low densities from birth onwards in control pancreata, while densities were higher in NOD and NODscid. Second, high numbers of BM8+ and ER-MP23+ Mphi were observed at birth in all strains investigated. After birth, particularly BM8+ cells disappeared progressively in control strains, but not in NOD and NODscid. Third, NOD mice also had more ER-MP23+ Mphi at birth compared to controls. Finally, DC and Mphi localizations were similar in all strains, i.e., mostly as dispersed cells in perivascular, periductular, peri-islet areas and interlobular septa. The most remarkable finding was that particularly BM8+ Mphi, were seen at sites of islet neogenesis and predominantly at the duct-islet interface. Our data showed that different types of APC were present in the pancreas during postnatal development in various control mouse strains and some differences were observed in NOD and NODscid mice from birth onwards.

/pdf/abnormalities-in-dendritic-cell-and-macrophage-accumulation-lkheogbsny.pdf

Abnormalities in dendritic cell and macrophage accumulation in the pancreas of nonobese diabetic (NOD) mice during the early neonatal period.

Regulation of tumor necrosis factor-α-mRNA synthesis and distribution of tumor necrosis factor-α-mRNA synthesizing cells in rat liver during experimental endotoxemia

The purpose of this investigation was to analyse the macrophage subpopulations involved in the uptake of endotoxin in the liver.

The role of macrophages in the uptake of endotoxin by the mouse liver.

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The role of macrophages in the uptake of endotoxin by the mouse liver.