Inhibitory Effect of Carotenoids on Ligand-induced Lipid Raft Translocation of Immunoreceptors

Abstract

Lipid rafts are microdomains present in the plasma membrane, which are enriched in sphingolipids and cholesterol. Certain kinases and adaptor proteins, which are important for cellular signaling, are also concentrated in lipid rafts. Several immunoreceptors are known to translocate into lipid rafts upon binding with their ligands to efficiently induce the signaling pathways, and hence, receptor translocation could be the new target for pleiotropic suppression of inflammatory responses. In this study, we evaluated the effects of carotenoids on ligand-induced lipid raft translocation of the receptors using B cell receptors (BCRs) as a model. Since all lipid raft-translocated BCRs were clustered at one pole of the cell, called capping, in our experimental condition, we screened the carotenoids for their inhibitory effect on lipid raft translocation of receptors using BCR capping as a parameter. Eleven out of twenty carotenoids significantly inhibited anti-IgM-induced BCR capping without cytotoxicity. Having no polar groups or a keto group at the C-8 position might be an important factor for inhibition. Treatment with lycopene, a non-polar carotenoid, and fucoxanthinol, a C-8-keto carotenoid, also suppressed lipopolysaccharide-induced translocation of Toll-like receptor 4 into lipid rafts, and subsequent nitric oxide production in RAW264 macrophages. These results indicated that some carotenoids, but not all, can modulate inflammatory responses via suppression of ligand-induced lipid raft translocation of immunoreceptors, and also showed that our assay using BCR capping has the potential for screening compounds that inhibit lipid raft translocation of receptors.