The effects of atorvastatin in experimental autoimmune uveitis.
OBJECTIVE
To investigate the effect of atorvastatin (Lipitor), a commonly used drug for dyslipidaemia in experimental autoimmune uveitis (EAU).


METHODS
48 B10-RIII mice were immunised with human interphotoreceptor retinoid binding protein (IRBP) peptide p161-180. They were divided into three groups of 16 each and treated orally once daily for 14 days; group one received phosphate buffered saline (control group), group two received 1 mg/kg of atorvastatin (low dose group), and group three received 10 mg/kg (high dose). On day 14 lymph nodes, spleens, and right eyes were harvested. RNA was extracted from lymph nodes for RNase protection assay (RPA) to determine proinflammatory (IL-1 alpha and IL-1 beta), Th1 (TNF-alpha, IL-2, IL-12), and Th2 (IL-4, IL-5, and IL-10) cytokine levels. Protein was extracted from spleens for western blot to detect the expression of phosphorylated signal transducer and activator of transcription (STAT) 4 and STAT6. The severity of inflammation in enucleated eyes was graded by a masked observer. Paired t test was performed for the mean difference in histological scoring between treated groups and the immunised control group.


RESULTS
Surprisingly, atorvastatin did not modulate the immune response. The proinflammatory cytokines, IL-1 alpha and IL-1 beta, and Th1 cytokines, TNF-alpha and IL-2, were upregulated equally in control and atorvastatin treated groups. IL-12 and Th2 cytokines were not upregulated in all three groups. Western blot analysis showed high levels of phosphorylated STAT4, but not STAT6 protein in the control and atorvastatin treated groups. Mean differences in histological scoring between treated groups and the immunised control group were not statistically significant.


CONCLUSIONS
Atorvastatin treatment had no effect on Th1 and Th2 cytokine transcription. Although histological grading suggested mildly decreased inflammation in the high dose treated group, the equivalence of cytokine expression in all groups suggests that the statins may not modulate IRBP induced uveoretinitis.
Thomas
P B
PB
The A Ray Irvine Ocular Pathology Laboratory, Doheny Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Albini
T
T
Giri
R K
RK
See
R F
RF
Evans
M
M
Rao
N A
NA
D000818:Animals; D000069059:Atorvastatin; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D015153:Blotting, Western / Q000379:methods; D004268:DNA-Binding Proteins / Q000032:analysis; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007375:Interleukin-1 / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D011758:Pyrroles / Q000494:pharmacology*; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015534:Trans-Activators / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology
D004268:DNA-Binding Proteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007375:Interleukin-1; D007376:Interleukin-2; D011758:Pyrroles; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D000069059:Atorvastatin
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