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

• Published in: The American journal of pathology Vol. 174; no. 4; pp. 1390 - 1399
• Main Authors: Lalazar, Gadi, Ya'acov, Ami Ben, Livovsky, Dan M, El Haj, Madi, Pappo, Orit, Preston, Sarah, Zolotarov, Lidya, Ilan, Yaron
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2009; American Society for Investigative Pathology
• Subjects: Animals; Antigens, CD1d - immunology; Antigens, CD1d - metabolism; Blotting, Western; Glycosphingolipids - immunology; Glycosphingolipids - metabolism; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Male; Membrane Proteins - immunology; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Pathology; Regular; Signal Transduction - physiology; STAT Transcription Factors - immunology; STAT Transcription Factors - metabolism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.080841

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 α- 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.