Pantethine Alters Lipid Composition and Cholesterol Content of Membrane Rafts, With Down-Regulation of CXCL12-Induced T Cell Migration.
Pantethine, a natural low-molecular-weight thiol, shows a broad activity in a large range of essential cellular pathways. It has been long known as a hypolipidemic and hypocholesterolemic agent. We have recently shown that it exerts a neuroprotective action in mouse models of cerebral malaria and Parkinson's disease through multiple mechanisms. In the present study, we looked at its effects on membrane lipid rafts that serve as platforms for molecules engaged in cell activity, therefore providing a target against inappropriate cell response leading to a chronic inflammation. We found that pantethine-treated cells showed a significant change in raft fatty acid composition and cholesterol content, with ultimate downregulation of cell adhesion, CXCL12-driven chemotaxis, and transendothelial migration of various T cell types, including human Jurkat cell line and circulating effector T cells. The mechanisms involved include the alteration of the following: (i) CXCL12 binding to its target cells; (ii) membrane dynamics of CXCR4 and CXCR7, the two CXCL12 receptors; and (iii) cell redox status, a crucial determinant in the regulation of the chemokine system. In addition, we considered the linker for activation of T cells molecule to show that pantethine effects were associated with the displacement from the rafts of the acylated signaling molecules which had their palmitoylation level reduced.. In conclusion, the results presented here, together with previously published findings, indicate that due to its pleiotropic action, pantethine can downregulate the multifaceted process leading to pathogenic T cell activation and migration.
Aix Marseille University, CNRS, NICN UMR 7259, Marseille, France.
Manuel
M
van Gijsel-Bonnello
INRA UMR 6265, University of Burgundy, Dijon, France.
Niyazi
N
Acar
Vect-Horus, 51 Boulevard Pierre Dramard, Marseille, France.
Yves
Y
Molino
INRA UMR 6265, University of Burgundy, Dijon, France.
Lionel
L
Bretillon
Aix Marseille University, CNRS, NICN UMR 7259, Marseille, France.
Michel
M
Khrestchatisky
Aix Marseille University, CNRS, NICN UMR 7259, Marseille, France.
Max
M
de Reggi
Aix Marseille University, CNRS, NICN UMR 7259, Marseille, France.
Bouchra
B
Gharib
D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D019169:Jurkat Cells; D008055:Lipids / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects*; D010204:Pantetheine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D054377:Chemokine CXCL12; D008055:Lipids; D010204:Pantetheine; C005425:pantethine; D002784:Cholesterol