Glucocerebroside treatment ameliorates ConA hepatitis by inhibition of NKT lymphocytes

Abstract

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.

Phosphorescence Oxygen Analyzer as a Measuring Tool for Cellular Bioenergetics

“…The hepatic injury is typically noted within 3 hr of intravenous injection of > 1.5 mg/kg of Con A and progresses with time (Tiegs et al, 1992). Activation and recruitment of Natural Killer (NK) T-cells and other cells of the innate immune system are early events, which lead to increased secretion of various inflammatory cytokines (e.g., TNF-, IL-2, IL-10, IL-12 and IFN-) (Takeda et al, 2000;Margalit et al, 2005;Chen et al, 2010;Sass et al, 2002). This immune response targets multiple organs including the liver.…”

Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

“…71 ConA induces liver damage that is mediated by natural killer T (NKT) cells. Serum aspartate aminotransferase and alanine aminotransferase levels were markedly lower, and histological damage was attenuated, in GC-treated mice compared with untreated animals.…”

“…Intraperitoneally administered radioactive GC could be detected in the liver and bowel. 71 Furthermore, the in vitro treatment of NKT cells with GC led to a 42% decrease in cell proliferation in the presence, but not absence, of dendritic cells (DCs).…”

“…120 b-Glycosphingolipids seem to affect NKT cells differently than does a-GalCer; b-glycosphingolipids inhibit NKT cell proliferation without stimulating cytokine expression. 71 …”

“…Indeed studies have shown that the immunomodulatory effect of GC is dependent on DCs. 71 Similarly, other glycospingolipids, such as a-GalCer, have been shown to alter the DC-NKT cell cross talk or to affect other regulatory T cells (Tregs). 133,134 GC promotes regulatory T cells Recent studies have suggested that glycosphingolipids can promote Tregs.…”