Published online before print February 26, 2009

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(American Journal of Pathology. 2009;174:1390-1399.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080841

β-Glycoglycosphingolipid-Induced Alterations of the STAT Signaling Pathways Are Dependent on CD1d and the Lipid Raft Protein Flotillin-2

Gadi Lalazar^*, Ami Ben Ya'acov^*, Dan M. Livovsky^*, Madi El Haj^*, Orit Pappo, Sarah Preston^*, Lidya Zolotarov^* and Yaron Ilan^*

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

β-glucosylceramide has been shown to affect natural killer T cell function in models of inflammation. We, therefore, investigated the effects of different β- glycosphingolipids, including β-glucosylceramide, on STAT (signal transducers and activators of transcription) signaling pathways and determined whether these effects were mediated by lipid raft microdomains and/or CD1d molecules. The effects of - and β-structured ligands on the lipid raft protein flotillin-2 were studied in both natural killer T hybridoma cells and leptin-deficient mice. To determine whether CD1d was involved in the effects of the β-glycosphingolipids, an anti-CD1d blocking antibody was used in a cell proliferation assay system. The downstream effects on the protein phosphorylation levels of STAT1, STAT3, and STAT6 were examined in both immune-mediated hepatitis and hepatoma models. The effects of β-glycosphingolipids on the STAT signaling pathways were found to be dependent on CD1d. Lipid rafts were affected by both the dose and ratio of the β-glycosphingolipids and the acyl chain length, and these effects were followed by downstream effects on STAT proteins. Our results show that β-glycosphingolipids have beneficial effects in natural killer T cell-dependent immune-mediated metabolic and malignant animal models in vivo.