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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Classical and alternative activation of rat hepatic sinusoidal endothelial cells by inflammatory stimuli.

Authors: Liu, Yinglin; Gardner, Carol R; Laskin, Jeffrey D; Laskin, Debra L

Published In Exp Mol Pathol, (2013 Feb)

Abstract: The ability of rat hepatic sinusoidal endothelial cells (HSEC) to become activated in response to diverse inflammatory stimuli was analyzed. Whereas the classical macrophage activators, IFNýý and/or LPS upregulated expression of iNOS in HSEC, the alternative macrophage activators, IL-10 or IL-4+IL-13 upregulated arginase-1 and mannose receptor. Similar upregulation of iNOS and arginase-1 was observed in classically and alternatively activated Kupffer cells, respectively. Removal of inducing stimuli from the cells had no effect on expression of these markers, demonstrating that activation is persistent. Washing and incubation of IFNýý treated cells with IL-4+IL-13 resulted in decreased iNOS and increased arginase-1 expression, while washing and incubation of IL-4+IL-13 treated cells with IFNýý resulted in decreased arginase-1 and increased iNOS, indicating that classical and alternative activation of the cells is reversible. HSEC were more sensitive to phenotypic switching than Kupffer cells, suggesting greater functional plasticity. Hepatocyte viability and expression of PCNA, ýý-catenin and MMP-9 increased in the presence of alternatively activated HSEC. In contrast, the viability of hepatocytes pretreated for 2 h with 5 mM acetaminophen decreased in the presence of classically activated HSEC. These data demonstrate that activated HSEC can modulate hepatocyte responses following injury. The ability of hepatocytes to activate HSEC was also investigated. Co-culture of HSEC with acetaminophen-injured hepatocytes, but not control hepatocytes, increased the sensitivity of HSEC to classical and alternative activating stimuli. The capacity of HSEC to respond to phenotypic activators may represent an important mechanism by which they participate in inflammatory responses associated with hepatotoxicity.

PubMed ID: 23103612 Exiting the NIEHS site

MeSH Terms: Acetaminophen/pharmacology; Animals; Arginase/biosynthesis; Cells, Cultured; Coculture Techniques; Endothelial Cells/drug effects; Endothelial Cells/physiology*; Hepatocytes/drug effects; Hepatocytes/physiology*; Inflammation; Interferon-gamma/pharmacology; Interleukin-10/pharmacology; Interleukin-13/pharmacology; Interleukin-4/pharmacology; Kupffer Cells/drug effects; Kupffer Cells/physiology*; Lectins, C-Type/biosynthesis; Lipopolysaccharides/pharmacology; Liver/cytology*; Liver/drug effects; Liver/metabolism*; Macrophage Activation*; Male; Mannose-Binding Lectins/biosynthesis; Matrix Metalloproteinase 9/biosynthesis; Nitric Oxide Synthase Type II/biosynthesis; Proliferating Cell Nuclear Antigen/biosynthesis; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface/biosynthesis; beta Catenin/biosynthesis

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