Atorvastatin affects TLR4 clustering via lipid raft modulation.
Statins, HMG-CoA reductase inhibitors, are used widely in the treatment of hypercholesterolemia. Apart from lowering lipid levels, statins have been shown to have anti-inflammatory effects. Previously we showed that atorvastatin inhibits NF-kappaB activation, dose and time dependently, in LPS-TLR4 signaling pathway. In this study, we investigated the anti-inflammatory mechanism of atorvastatin via Toll-like receptor 4 (TLR4) in murine pro-B cell lines transfected with TLR4. Co-treatment of LPS-stimulated cells with both atorvastatin and mevalonate rescued NF-kappaB activation and TLR4 blockade demonstrated that atorvastatin does not exert its inhibitory effect via TLR4 receptor-ligand binding mechanism. Further investigation into the anti-inflammatory mechanism has shown that atorvastatin causes an impairment of TLR4 recruitment into the lipid raft thereby affecting anti-inflammatory responses. In contrast, mevalonate repaired lipid raft function leading to TLR4 clustering in the lipid raft. Together, these data suggest that atorvastatin exerts its anti-inflammatory effect via lipid raft modification. This novel finding offers another insight into the pleiotropic effects of atorvastatin and may be applicable to other pattern recognition receptors that utilize membrane lipid raft as a platform for signal transduction.
Chansrichavala
Praveen
P
Department of Pharmacology, Faculty of Science, Mahidol University, Rama VI Rd., Bangkok 10400, Thailand.
Chantharaksri
Udom
U
Sritara
Piyamitr
P
Ngaosuwankul
Nathamon
N
Chaiyaroj
Sansanee C
SC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019138:Antibodies, Blocking / Q000494:pharmacology; D000069059:Atorvastatin; D002460:Cell Line; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D011940:Receptor Aggregation / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D019138:Antibodies, Blocking; D006538:Heptanoic Acids; D008070:Lipopolysaccharides; D011758:Pyrroles; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000069059:Atorvastatin; D008798:Mevalonic Acid