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Atorvastatin Affects Interleukin-2 Signaling by Altering the Lipid Raft Enrichment of the Interleukin-2 Receptor β Chain
  1. Jens Goebel,
  2. Barbara Logan,
  3. Kathy Forrest,
  4. Alexandra Mieczkowski,
  5. Thomas L. Roszman,
  6. Marsha Wills-Karp
  1. From the Divisions of Nephrology and Hypertension (J.G., B.L., A.M.) and Immunobiology (M.W.-K.), Cincinnati Children's Hospital, Cincinnati, OH, and Departments of Pediatrics (J.G., K.F.) and Immunology (T.L.R.), University of Kentucky, Lexington, KY. Supported by National Institutes of Health KO8 grant A1049241, a National Kidney Foundation Young Investigator Award, a University of Kentucky Physician-Scientist award, and by funds from the University of Kentucky Department of Pediatrics, all to J.G. Presented in part at the American Federation for Medical Research-sponsored symposium during Experimental Biology 2005, San Diego, CA, April 2-6, 2005, and in part at the meeting of the International Pediatric Transplantation Society, Rio de Janeiro, Brazil, April 5-9, 2003; the American Transplant Congress, Boston, MA, May 14-19, 2004; and the meeting of the American Society of Nephrology, St. Louis, MO, October 29-November 1, 2004.
  1. Address correspondence to: Dr. Jens Goebel, Cincinnati Children's Hospital Medical Center, Nephrology and Hypertension, MLC 7022, 3333 Burnet Avenue, Cincinnati, OH 45229-3039; e-mail: Jens.Goebel{at}cchmc.org .

Abstract

ABSTRACT 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) β 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 α 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 β chain. Although this AS-associated increase in GM-1 expression resembled that seen in the presence of the raft-disrupting cholesterol chelator methyl-β-cyclodextrin (MBCD), the two agents had contrasting effects on the tyrosine phosphorylation of the IL-2R β 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 β chain and propose that this effect is one mechanism underlying the immunomodulatory properties of statins.

Key Words
  • statins
  • rafts
  • interleukin-2 receptor

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