Lactosylceramide recruits PKCalpha/epsilon and phospholipase A2 to stimulate PECAM-1 expression in human monocytes and adhesion to endothelial cells
| Autor: | Sanaul Haq Chowdhury, Subroto Chatterjee, NanLing Gong, Heming Wei |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Protein Kinase C-alpha
Transcription Genetic Lactosylceramides Protein Kinase C-epsilon Biology Monocytes Phospholipases A chemistry.chemical_compound Lactosylceramide Phospholipase A2 Antigens CD Cell Adhesion Animals Humans Enzyme Inhibitors Cell adhesion music Protein kinase C Protein Kinase C Multidisciplinary music.instrument Arachidonic Acid U937 cell U937 Cells Biological Sciences Cell biology Up-Regulation Nordihydroguaiaretic acid Enzyme Activation Platelet Endothelial Cell Adhesion Molecule-1 Phospholipases A2 chemistry biology.protein Prostaglandins Arachidonic acid lipids (amino acids peptides and proteins) Cattle Endothelium Vascular Intracellular |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 101(17) |
| ISSN: | 0027-8424 |
| Popis: | Despite the importance of platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31) in the adhesion and diapedesis of monocytes/lymphocytes, little is known about the mechanisms by which it is regulated. We explored the role of a glycosphingolipid, lactosylceramide (LacCer), in modulating PECAM-1 expression and cell adhesion in human monocytes. We observed that LacCer specifically exerted a time-dependent increase in PECAM-1 expression in U-937 cells. Maximal increase in PECAM-1 protein occurred after incubation with LacCer for 60 min. LacCer activated PKCα and -ε by translocating them from cytosol to membrane. This was accompanied by the activation of phospholipase A2(PLA2) and the increase of cell adhesion, which were abrogated by chelerythrine chloride, 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide and 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (GÖ 6976) (PKC inhibitors). Similarly, bromoenol lactone (a Ca2+-independent PLA2inhibitor) and methyl arachidonyl fluorophosphonate (an inhibitor of cytosolic PLA2and Ca2+-independent PLA2) inhibited LacCer-induced PLA2activity. Bromophenacyl bromide (a PLA2inhibitor) abrogated LacCer-induced PECAM-1 expression, and this was bypassed by arachidonic acid. Furthermore, the arachidonate-induced up-regulation of PECAM-1 was abrogated by indomethacin [a cyclooxygenase (COX)-1 and -2 inhibitor] orN-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (a COX-2 inhibitor) but not nordihydroguaiaretic acid (a lipoxygenase inhibitor). In sum, PKCα/ε are the primary targets for the activation of LacCer. Downstream activation of intracellular Ca2+-independent PLA2and/or cytosolic PLA2results in the production of arachidonic acid, which in turn serves as a precursor for prostaglandins that subsequently stimulate PECAM-1 expression and cell adhesion. These findings may be relevant in explaining the role of LacCer in the regulation of PECAM-1 and related pathophysiology. |
| Databáze: | OpenAIRE |
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