Fas Regulates Macrophage Polarization and Fibrogenic Phenotype in a Model of Chronic Ethanol-Induced Hepatocellular Injury.
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.
Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.
Fuyumi
F
Isayama
Department of Nutrition Science, College of Allied Health, East Carolina University, Greenville, North Carolina.
Sherri
S
Moore
Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina; Department of Nutrition Science, College of Allied Health, East Carolina University, Greenville, North Carolina.
Ian N
IN
Hines
Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina; Department of Nutrition Science, College of Allied Health, East Carolina University, Greenville, North Carolina. Electronic address: wheelerm@ecu.edu.
Michael D
MD
Wheeler
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D019014:fas Receptor