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Journal of Lipid Research, Vol. 49, 1884-1893, September 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

β-Glycosphingolipids-mediated lipid raft alteration is associated with redistribution of NKT cells and increased intrahepatic CD8⁺ T lymphocyte trapping

Gadi Lalazar^1,*, Ami Ben Ya'acov^1,*, Noa Eliakim-Raz^*, Dan M. Livovsky^*, Orit Pappo, Sarah Preston^*, Lidya Zolotarov^* and Yaron Ilan^2,*

^* Liver Unit, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
Department of Pathology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

Published, JLR Papers in Press, May 15, 2008.

This work was supported in part by a grant from The Roman-Epstein Liver Research Foundation (Y. I.).

¹ G. Lalazar and A. Ben Ya'acov contributed equally to this work.

² To whom correspondence should be addressed. e-mail: ilan{at}hadassah.org.il

The aim of this study was to determine the effect of β-glycosphingolipids on intra-hepatic natural killer T (NKT) lymphocyte regulatory function and on lymphocyte trapping via alteration of cell membrane lipid rafts. Immune-mediated colitis was induced by intracolonic instillation of trinitrobenzene sulfonic acid. Mice were treated with β-lactosylceramide (LC), β-glucosylceramide (GC), β-galactosylceramide, ceramide, or a combination of both GC and LC (IGL), or solvent alone. Lipid rafts were investigated by fluorescence-activated cell sorting analysis of ganglioside-GM1 and fluorescence microscopy of structure. Administration of β-glycosphingolipids resulted in an increased intrahepatic/peripheral NKT ratio, increased intrahepatic CD8+ lymphocyte trapping, decreased serum interferon- (IFN-) levels and decreased serum IFN-/interleukin-10 ratio. Administration of GC, LC, or IGL significantly altered the levels of GM1, a key marker of lipid rafts, on NKT regulatory lymphocytes. The immune modulatory effect of β-glycosphingolipids was associated with increased survival and significant alleviation of colitis as determined by improvement in both the macroscopic and microscopic scores. In conclusion, administration of β-glycosphingolipids increased NKT regulatory lymphocyte redistribution and intrahepatic CD8⁺ T lymphocyte trapping, resulting in alleviation of immune-mediated colitis. The effects of these naturally occurring compounds were associated with modification of the T lymphocyte lipid raft structure, which is a site for immune modulation.

Supplementary key words liver tolerance • lipid rafts • natural killer T cell

Abbreviations: APC, antigen-presenting cell; CTx, cholera toxin; FACS, fluorescence-activated cell sorting; -GalCer, -galactosylceramide; GC, β-glucosylceramide; GLC, β-galactosylceramide; IFN-, interferon-; IGL, β-glucosylceramide + β-lactosylceramide; IL-4, interleukin-4; LC, β-lactosylceramide; MHC, major histocompatibility complex; NKT cell, natural killer T cell; TCR, T cell receptor; TNBS, trinitrobenzene sulfonic acid

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