Failure of oral atorvastatin to modulate a murine model of systemic lupus erythematosus.
OBJECTIVE
Inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase enzyme (statins) are cholesterol-lowering drugs that have shown promise as therapeutic agents in various animal models of autoimmune disease. The results of initial clinical trials with statins in multiple sclerosis and rheumatoid arthritis have also been encouraging. In this study, we attempted to treat a widely studied murine model of spontaneous systemic lupus erythematosus (SLE) with atorvastatin.


METHODS
(NZB x NZW)F1 (NZB/NZW) mice received daily oral doses of atorvastatin for 20 weeks. The mice were monitored weekly for survival and proteinuria. Anti-double-stranded DNA (anti-dsDNA) antibody levels in sera were determined by enzyme-linked immunosorbent assay (ELISA). T lymphocyte cytokine production in vitro, as well as cytokine levels in vivo, were measured by ELISA. T cell proliferation was assessed by thymidine incorporation assay. Serum cholesterol levels were determined using a standard fluorometric assay. Kidney tissue was harvested and evaluated for pathologic changes.


RESULTS
In NZB/NZW mice, oral atorvastatin had significant effects on T cell proliferation and cytokine production in vitro. Atorvastatin also induced significant increases in serum levels of interleukin-4. However, atorvastatin treatment in NZB/NZW mice had no significant impact on proteinuria, survival, serum anti-dsDNA antibody and cholesterol levels, or extent of renal disease.


CONCLUSIONS
Monotherapy with oral atorvastatin has no protective effects in a murine model of spontaneous SLE. The efficacy of atorvastatin in human SLE remains to be determined.
Graham
Kareem L
KL
Stanford University School of Medicine, Stanford, California 94305, USA.
Lee
Lowen Y
LY
Higgins
John P
JP
Steinman
Lawrence
L
Utz
Paul J
PJ
Ho
Peggy P
PP
D000284:Administration, Oral; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000069059:Atorvastatin; D049109:Cell Proliferation / Q000187:drug effects*; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D015847:Interleukin-4 / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy*; D051379:Mice; D008814:Mice, Inbred NZB; D011758:Pyrroles / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000187:drug effects*; D016896:Treatment Outcome
D000974:Antibodies, Antinuclear; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D015847:Interleukin-4; D002784:Cholesterol; D000069059:Atorvastatin