Statins induce regulatory T cell recruitment via a CCL1 dependent pathway.
The statins, a group of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are reported to influence a variety of immune system activities through 3-hydroxy-3-methylglutaryl coenzyme A reductase-dependent and -independent mechanisms. How statin treatment regulates immune system function in vivo nonetheless remains to be fully defined. We analyzed the immunomodulatory effects of lovastatin in a Candida albicans-induced delayed-type hypersensitivity reaction in mice. In this model, lovastatin administration reduced the acute inflammatory response elicited by C. albicans challenge. This anti-inflammatory activity of lovastatin was associated with a shift from a Th1 to a Th2 immune response, as well as an increase in the percentage of regulatory T cells at the inflammation site and in the regional draining lymph node. The lovastatin-induced increase in regulatory T cells in the inflamed skin was dependent on expression of CCL1, a chemokine that is locally up-regulated by statin administration. The anti-inflammatory effect of lovastatin was abrogated in CCL1-deficient mice. These results suggest that local regulation of chemokine expression may be an important process in statin-induced modulation of the immune system.
Mira
Emilia
E
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain.
León
Beatriz
B
Barber
Domingo F
DF
Jiménez-Baranda
Sonia
S
Goya
Iñigo
I
Almonacid
Luis
L
Márquez
Gabriel
G
Zaballos
Angel
A
Martínez-A
Carlos
C
Stein
Jens V
JV
Ardavín
Carlos
C
Mañes
Santos
S
D000818:Animals; D002176:Candida albicans / Q000276:immunology; D054402:Chemokine CCL1 / Q000235:genetics*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006967:Hypersensitivity / Q000382:microbiology / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008148:Lovastatin / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000502:physiology; D018418:Th2 Cells / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
C502258:Ccl1 protein, mouse; D054402:Chemokine CCL1; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin