Atorvastatin affects interleukin-2 signaling by altering the lipid raft enrichment of the interleukin-2 receptor beta chain.
Although the immunomodulatory properties of statins are in part independent of their lipid-lowering effects, cholesterol is a major component of lipid rafts. We therefore studied the effects of atorvastatin (AS) on the raft enrichment of the interleukin-2 receptor (IL-2R) beta chain previously described by us and on early IL-2R signaling events in activated human T cells. We found that concomitant AS exposure during a 3-day stimulation with phytohemagglutinin (PHA) attenuates activation-associated events, such as the enhanced surface expression of the raft marker GM-1 and the induced expression of the activation marker CD25 (the IL-2R alpha chain). In contrast, brief AS treatment after PHA stimulation increased GM-1 surface expression and virtually abolished the selective raft enrichment of the IL-2R beta chain. Although this AS-associated increase in GM-1 expression resembled that seen in the presence of the raft-disrupting cholesterol chelator methyl-beta-cyclodextrin (MBCD), the two agents had contrasting effects on the tyrosine phosphorylation of the IL-2R beta chain by exogenous IL-2: MBCD essentially abolished this event, whereas AS tended to enhance it and shifted its occurrence out of rafts. We conclude that AS affects IL-2R signaling by altering the raft enrichment of the IL-2R beta chain and propose that this effect is one mechanism underlying the immunomodulatory properties of statins.
Goebel
Jens
J
Division of Nephrology and Hypertension, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA. Jens.Goebel@cchmc.org
Logan
Barbara
B
Forrest
Kathy
K
Mieczkowski
Alexandra
A
Roszman
Thomas L
TL
Wills-Karp
Marsha
M
D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000378:metabolism*; D053646:Interleukin-2 Receptor beta Subunit; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D018123:Receptors, Interleukin / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; C508020:IL2RB protein, human; D007155:Immunologic Factors; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D011758:Pyrroles; D018123:Receptors, Interleukin; D000069059:Atorvastatin