Effects of Cytokine Antagonists on the Hepatic Acute-Phase Response

Mazuski, John E.; Tolman, Kim; Shapiro, Marc J.

doi:10.1006/jsre.1997.4999

Cited by 14 publications

(17 citation statements)

References 42 publications

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“…DNA microarray analysis shows that LPS exposure leads to the upand downregulation of a number of genes in cultured hepatocytes (Tables 2 and 3). Studies over the past few years have suggested that hepatocytes can respond directly to microbial products (33,40,56). The effect of LPS in vivo on hepatic function is also well known.…”

Section: Discussionmentioning

confidence: 99%

Role of Toll-Like Receptors in Changes in Gene Expression and NF-κB Activation in Mouse Hepatocytes Stimulated with Lipopolysaccharide

et al. 2002

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The liver is an important site of host-microbe interaction. Although hepatocytes have been reported to be responsive to lipopolysaccharide (LPS), the global gene expression changes by LPS and mechanism(s) by which LPS stimulates cultured hepatocytes remain uncertain. Cultures of primary mouse hepatocytes were incubated with LPS to assess its effects on the global gene expression, hepatic transcription factors, and mitogen-activated protein (MAP) kinase activation. DNA microarray analysis indicated that LPS modulates the selective expression of more than 80 genes and expressed sequence tags. We have shown previously that hepatocytes express CD14, which is required both for uptake and responsiveness to LPS. In other cells, responsiveness to microbial products requires expression of Toll-like receptors (TLR) and their associated accessory molecules. Hepatocytes expressed TLR1 through TLR9 as well as MyD88 and MD-2 transcripts, as shown by reverse transcriptase PCR analysis, indicating that hepatocytes express all known microbe recognition molecules. The MAP kinase extracellular signal-regulated kinase 1/2 was phosphorylated in response to LPS in mouse hepatocytes, and the levels of phosphorylation were lower in hepatocytes from TLR4-null mice. NF-B activation was reduced in TLR4-mutant or -null hepatocytes compared to control hepatocytes, and this defect was partially restored by adenoviral transduction of mouse TLR4. Thus, hepatocytes respond to nanogram concentrations of LPS through a TLR4 response pathway.Lipopolysaccharide (LPS), a glycolipid constituent of the outer membrane of gram-negative bacteria, initiates signaling cascades in cells such as macrophages and endothelial cells, leading to the release of cytokines and other inflammatory mediators during sepsis. Excessive production of these mediators can cause septic shock and multiple organ failure (55).A decade ago, CD14, a 55-kDa glycoprotein and monocyte differentiation antigen, was identified as an important LPS recognition molecule (60). CD14 alone, however, is unable to transduce the intracellular LPS signal, since CD14 is only tethered to the cytoplasmic membrane by a glycosyl phosphatidylinositol anchor and lacks a membrane-spanning domain (17). Members of a family of proteins, the mammalian homologues of the Drosophila Toll protein, were found to act as transmembrane coreceptors to CD14 in the cellular response to LPS (34). These Toll-like receptors (TLR) contain ectodomains with leucine-rich repeats, and their intracellular motifs are highly homologous to intracellular signaling domains of interleukin-1 receptor type I (IL-1RI) and IL-1RI accessory protein (reviewed in reference 5). Following dimerization of the TLR, these domains attract the adapter protein MyD88, which in turn recruits the IL-1R-associated kinase. Following this association, IL-1R-associated kinase phosphorylates tumor necrosis factor receptor-associated factor 6, which in turn attracts two more protein tyrosine kinases, transforming growth factor beta-activated kinase 1 (TAK-1)...

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Section: Discussionmentioning

confidence: 99%

Role of Toll-Like Receptors in Changes in Gene Expression and NF-κB Activation in Mouse Hepatocytes Stimulated with Lipopolysaccharide

et al. 2002

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“…These hepatocyte preparations are at least 99% free of contaminating hepatic nonparenchymal cells as determined by periodic acid-Schiff's staining and by immunofluorescent analysis for I a and Mac-1 markers. The cells were cultured in microwells at an initial cell density of 30,000 cells/well in 0.1 ml of culture medium, as described previously [16,19]. For most experiments, the medium contained no dexamethasone, but in a few experiments, the hepatocytes were maintained continuously in culture medium containing various concentrations of dexamethasone.…”

Section: Methodsmentioning

confidence: 99%

“…Unelicited peritoneal macrophages were obtained as described previously [19] and cultured in microwells at a concentration of 128,000 cells/well in 100 l of MEM containing 5% fetal calf serum. After 24 h, the cultures were treated with control medium or medium containing 10 g/ml of LPS for an additional 24 h. The supernatant medium was then collected and stored at Ϫ70°until assayed for IL-6 concentrations.…”

Section: Methodsmentioning

confidence: 99%

“…Hepatocytes were isolated from the livers of these mice using a modification of the technique of Seglen [20], as described previously [16,19]. These hepatocyte preparations are at least 99% free of contaminating hepatic nonparenchymal cells as determined by periodic acid-Schiff's staining and by immunofluorescent analysis for I a and Mac-1 markers.…”

Section: Methodsmentioning

confidence: 99%

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Endotoxin Stimulates Hepatocyte Interleukin-6 Production

Panesar

Tolman²,

Mazuski³

1999

Journal of Surgical Research

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“…Peptides have been designed with α-helix organization to neutralizelipopolysaccharide endotoxins [13]- [15] with relevance to the binding of apo E to Aβ. Furthermore, LPS alter hepatic lipid metabolism with an increase hepatic cytokines and APPs in plasma that are involved in LPS inactivation [16]- [23] associated with Aβ dyshomeostasis [3]. Lipoproteins such as chylomicrons that are produced after a high fat diet contain the LPS binding protein (LBP) that bind LPS and essential interactions of LPS to apo B containing cholesterol-rich lipoproteins [4] clearly implicate dietary fat and LPS in peripheral Aβ metabolism in diabetes with relevance to neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

LPS Regulates Apolipoprotein E and A<i>β</i> Interactionswith Effects on Acute Phase Proteins and Amyloidosis

Martins¹

2015

AAR

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Interactions between apolipoprotein E (apo E) and amyloid beta (Aβ) are associated with the peripheral clearance of Aβ and are important to the development of neurodegenerative diseases. Interests in acute phase proteins (APP) as biomarkers for the early progression of Alzheimer's disease indicate that the peripheral Aβ metabolism is perturbed and the role of nutritional diets are important to reduce APPs to maintain peripheral Aβ clearance with relevance to hepatic cholesterol homeostasis and brain amyloidosis. The role of nutriproteomic diets that reverse the effects of high fat diets are associated with the reduction in APPs, cholesterol homeostasis and improved clearance of Aβ. Nutritional diets that reduce the increase in plasma endotoxins (gut microbiotica) such as lipopolysaccarides (LPS) reduce the effects of LPS on cell membranes and increase the cellular uptake of Aβ by interactions with apo E. LPS alter hepatic lipid metabolism with an increase hepatic cytokines and APPs in plasma. Interactions between apo E and Aβ are altered by LPS with increased binding of LPS to apo E with effects on electrostatic alterations in Aβ oligomers. The role of LPS in neurodegenerative diseases includes the effects of LPS on alpha-synuclein metabolism with relevance to Parkinson's disease and Alzheimer's disease.

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Effects of Cytokine Antagonists on the Hepatic Acute-Phase Response

Cited by 14 publications

References 42 publications

Role of Toll-Like Receptors in Changes in Gene Expression and NF-κB Activation in Mouse Hepatocytes Stimulated with Lipopolysaccharide

Role of Toll-Like Receptors in Changes in Gene Expression and NF-κB Activation in Mouse Hepatocytes Stimulated with Lipopolysaccharide

Endotoxin Stimulates Hepatocyte Interleukin-6 Production

LPS Regulates Apolipoprotein E and A<i>β</i> Interactionswith Effects on Acute Phase Proteins and Amyloidosis

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Effects of Cytokine Antagonists on the Hepatic Acute-Phase Response

Cited by 14 publications

References 42 publications

Role of Toll-Like Receptors in Changes in Gene Expression and NF-κB Activation in Mouse Hepatocytes Stimulated with Lipopolysaccharide

Role of Toll-Like Receptors in Changes in Gene Expression and NF-κB Activation in Mouse Hepatocytes Stimulated with Lipopolysaccharide

Endotoxin Stimulates Hepatocyte Interleukin-6 Production

LPS Regulates Apolipoprotein E and A&lt;i&gt;β&lt;/i&gt; Interactionswith Effects on Acute Phase Proteins and Amyloidosis

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LPS Regulates Apolipoprotein E and A<i>β</i> Interactionswith Effects on Acute Phase Proteins and Amyloidosis