Article ; Online: Fas Regulates Macrophage Polarization and Fibrogenic Phenotype in a Model of Chronic Ethanol-Induced Hepatocellular Injury.
The American journal of pathology
2016 Volume 186, Issue 6, Page(s) 1524–1536
Abstract: The role of Fas-mediated apoptosis and its effect on proinflammatory cytokine production in early alcoholic liver disease has not been addressed. Wild-type mice (C57Bl/6) or mice with a functional mutation in the Fas ligand (B6.gld) were given either ... ...
| Abstract | The role of Fas-mediated apoptosis and its effect on proinflammatory cytokine production in early alcoholic liver disease has not been addressed. Wild-type mice (C57Bl/6) or mice with a functional mutation in the Fas ligand (B6.gld) were given either high-fat control diet or ethanol diet by intragastric cannulation for 2 or 4 weeks. Liver injury, hepatic lipid accumulation, and proinflammatory cytokine production associated with chronic ethanol consumption were largely prevented in B6.gld mice compared with wild-type mice. Conversely, B6.gld mice given ethanol exhibited increases in collagen deposition, hepatic collagen gene expression, and profibrogenic cytokines (eg, transforming growth factor-β and IL-13) and alterations in matrix remodeling proteins (eg, matrix metalloproteinases and tissue inhibitor of metalloproteinases) compared with wild-type mice. Hepatic F4/80(+) macrophage populations were increased significantly in B6.gld mice compared with wild-type mice; hepatic CD3(+) cell populations were not significantly different. Importantly, a shift toward the expression of M2/Th2 cytokines (eg, IL-4 and IL-13) after ethanol exposure was observed in B6.gld mice compared with classical M1 cytokine expression in wild-type mice under similar conditions. In isolated macrophages, stimulation of Fas receptor minimally enhances lipopolysaccharide-induced M1 cytokine production and significantly limits M2 cytokine production. These data support the hypothesis that Fas-mediated signaling is important for an early ethanol-induced proinflammatory response but limits the profibrogenic response, regulating collagen production in response to chronic ethanol. |
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| MeSH term(s) | Animals ; Apoptosis/physiology ; Blotting, Western ; Disease Models, Animal ; Fas Ligand Protein/metabolism ; Immunohistochemistry ; In Situ Nick-End Labeling ; Liver Cirrhosis/metabolism ; Liver Cirrhosis/pathology ; Liver Diseases, Alcoholic/metabolism ; Liver Diseases, Alcoholic/pathology ; Macrophages/cytology ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Phenotype ; Real-Time Polymerase Chain Reaction ; fas Receptor/metabolism |
| Chemical Substances | Fas Ligand Protein ; Fas protein, mouse ; fas Receptor |
| Language | English |
| Publishing date | 2016 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 2943-9 |
| ISSN | 1525-2191 ; 0002-9440 |
| ISSN (online) | 1525-2191 |
| ISSN | 0002-9440 |
| DOI | 10.1016/j.ajpath.2016.02.006 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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