Beta-glycoglycosphingolipid-induced alterations of the STAT signaling pathways are dependent on CD1d and the lipid raft protein flotillin-2.
Beta-glucosylceramide has been shown to affect natural killer T cell function in models of inflammation. We, therefore, investigated the effects of different beta-glycosphingolipids, including beta-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 alpha- and beta-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 beta-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 beta-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 beta-glycosphingolipids and the acyl chain length, and these effects were followed by downstream effects on STAT proteins. Our results show that beta-glycosphingolipids have beneficial effects in natural killer T cell-dependent immune-mediated metabolic and malignant animal models in vivo.
Lalazar
Gadi
G
Liver Unit, Department of Medicine, Hebrew University-Hadassah Medical Center, P.O.B 12000, Jerusalem, Israel, IL-91120.
Ben Ya'acov
Ami
A
Livovsky
Dan M
DM
El Haj
Madi
M
Pappo
Orit
O
Preston
Sarah
S
Zolotarov
Lidya
L
Ilan
Yaron
Y
D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D006028:Glycosphingolipids / Q000276:immunology / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050791:STAT Transcription Factors / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D055610:Antigens, CD1d; D006028:Glycosphingolipids; D008565:Membrane Proteins; D050791:STAT Transcription Factors; C106354:flotillins