Glucocerebroside treatment ameliorates ConA hepatitis by inhibition of NKT lymphocytes.
Concanavalin A (ConA) induces natural killer T (NKT) cell-mediated liver damage. Glucocerebroside (GC) is a naturally occurring glycolipid. Our aims were to determine the effect of GC in a murine model of ConA-induced hepatitis. Mice in groups A and B were treated with GC 2 h before and 2 h following administration of ConA, respectively; group C mice were treated with ConA; group D mice was treated with GC; group E mice did not receive any treatment. Liver damage was evaluated by serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver histology. The immune effect of GC was determined by fluorescence-activated cell sorter analysis of intrahepatic and intrasplenic NKT lymphocytes, measurement of cytokine levels, and Western blot analysis for STAT 1, 4, 6, and NF-kappaB expression. The effect of GC on NKT cell proliferation was assessed in vitro. Serum AST and ALT levels were markedly reduced in GC-treated group A mice compared with nontreated group C animals, and histological damage was markedly attenuated in group A. The beneficial effect of GC was associated with a 20% decrease of intrahepatic NKT lymphocytes, significant lowering of serum IFN-gamma levels, and decreased STAT1 and STAT6 expression. In vitro administration of GC led to a 42% decrease of NKT cell proliferation in the presence of dendritic cells but not in their absence. Intraperitoneally administered radioactive GC was detected in the liver and bowel. Administration of GC led to amelioration of ConA hepatitis associated with an inhibitory effect on NKT lymphocytes. GC holds promise as a new immune-modulatory agent.
Liver Unit, Department of Medicine, Hadassah University Hospital, Jerusalem, Israel.
Maya
M
Margalit
Samir
S
Abu Gazala
Samir Abu
SA
Ghazala
Ruslana
R
Alper
Eran
E
Elinav
Athalia
A
Klein
Victoria
V
Doviner
Yoav
Y
Sherman
Barbara
B
Thalenfeld
Dean
D
Engelhardt
Elazar
E
Rabbani
Yaron
Y
Ilan
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003208:Concanavalin A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D003713:Dendritic Cells / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005963:Glucosylceramides / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis
D016207:Cytokines; D005963:Glucosylceramides; D014157:Transcription Factors; D003208:Concanavalin A