The effects of atorvastatin in experimental autoimmune uveitis

P Thomas

T Albini

R Giri

R See

M Evans

N Rao

^{The A Ray Irvine Ocular Pathology Laboratory, Doheny Eye Institute, and Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA}

^{The Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of southern California, Los Angeles, CA, USA}

Correspondence to:
Narsing A Rao
Doheny Eye Institute, DVRC 211, 1450 San Pablo Street, Los Angeles CA 90033, USA; ude.csu@oarn

Accepted 2004 Aug 3.

Abstract

Aim: 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-1α and IL-1β), Th1 (TNF-α, 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-1α and IL-1β, and Th1 cytokines, TNF-α 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.

Keywords: experimental autoimmune uveitis, atorvastatin

Abstract

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors or statins are widely used as hypolipidaemic drugs. Atorvastatin is the most widely used statin and is comparably well tolerated in patients. The major outcome in the use of these drugs is the decreased rate of coronary events.^1,² Recent studies have revealed the immunomodulatory effect of statins in mouse models of experimental autoimmune encephalomyelitis (EAE), a Th1 mediated autoimmune disorder.^3–⁵ In this model oral administration of atorvastatin at a dose of 1 mg/kg and 10 mg/kg profoundly modulated the Th1 to a Th2 response, which was associated with inhibition and reversal of chronic and relapsing encephalomyelitis.⁴ In addition to upregulating Th2 cytokines (IL-4, IL-5, and IL-10), atorvastatin induced signal transducer and activator of transcription (STAT) 6 tyrosine phosphorylation, which is associated with IL-4 upregulation. Conversely, STAT4 phosphorylation, associated with IL-12 induction, was inhibited and transcription of Th1 cytokines (IL-2, IL-12, interferon (IFN)-γ and TNF-α) was suppressed.

Although experimental autoimmune uveoretinitis (EAU) is also considered to be predominantly Th1 mediated,^6,⁷ it is known that Th2 mediated autoimmunity in EAU can also lead to significant retinal pathology in EAU.⁷ For this reason, in spite of many similarities between EAE and EAU, it was unclear what effect oral administration of atorvastatin would have in modulation of EAU. In the present study, we investigated the effects of atorvastatin on the Th1 and Th2 cytokine profiles and severity of uveitis in B10-RIII mice with EAU.

Abbreviations

EAE, experimental autoimmune encephalomyelitis
EAU, experimental autoimmune uveitis
IFN, interferon
IRBP, interphotoreceptor retinoid binding protein
RPA, RNase protection assay
STAT, signal transducer and activator of transcription

Abbreviations

Notes

Supported in part by National Eye Institute grant EY013253 and core grant 3040 from the National Institutes of Health, Bethesda, MD, USA.

Notes

Supported in part by National Eye Institute grant EY013253 and core grant 3040 from the National Institutes of Health, Bethesda, MD, USA.

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