Suppression of autoimmune retinal disease by lovastatin does not require Th2 cytokine induction.
Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In an acute mouse model of autoimmune retinal disease, we demonstrate that treatment with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, lovastatin, suppresses clinical ocular pathology, retinal vascular leakage, and leukocytic infiltration into the retina. Efficacy was reversed by coadministration of mevalonolactone, the downstream product of 3-hydroxy-3-methylglutaryl coenzyme A reductase, but not by squalene, which is distal to isoprenoid pyrophosphate metabolites within the cholesterol biosynthetic pathway. Lovastatin treatment (20 mg/kg/day i.p.) over 7 days, which resulted in plasma lovastatin hydroxyacid concentrations of 0.098 +/- 0.03 microM, did not induce splenocyte Th2 cytokine production but did cause a small reduction in Ag-induced T cell proliferation and a decrease in the production of IFN-gamma and IL-10. Thus, it is possible to dissociate the therapeutic effect of statins in experimental autoimmune uveitic mice from their activity on the Th1/Th2 balance. Statins inhibit isoprenoid pyrophosphate synthesis, precursors required for the prenylation and posttranslational activation of Rho GTPase, a key molecule in the endothelial ICAM-1-mediated pathway that facilitates lymphocyte migration. Consistent with inhibition of leukocyte infiltration in vivo, lovastatin treatment of retinal endothelial cell monolayers in vitro leads to inhibition of lymphocyte transmigration, which may, in part, account for drug efficacy. Unlike lovastatin, atorvastatin treatment showed little efficacy in retinal inflammatory disease despite showing significant clinical benefit in experimental autoimmune encephalomyelitis. These data highlight the potential differential activity of statins in different inflammatory conditions and their possible therapeutic use for the treatment of human posterior uveitis.
Harry
Rachel
R
Division of Clinical Ophthalmology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL, UK.
Gegg
Matthew
M
Division of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL, UK.
Hankey
Deborah
D
Department of Neuroinflammation, Institute of Neurology, University College London, 1 Wakefield Street, London, WC1N 1PJ, UK.
Zambarakji
Hadi
H
Vitreoretinal Unit, Moorfields Eye Hospital, London, EC1V 2PD, UK.
Pryce
Gareth
G
Department of Neuroinflammation, Institute of Neurology, University College London, 1 Wakefield Street, London, WC1N 1PJ, UK.
Baker
David
D
Department of Neuroinflammation, Institute of Neurology, University College London, 1 Wakefield Street, London, WC1N 1PJ, UK.
Calder
Virginia
V
Division of Clinical Ophthalmology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL, UK.
Adamson
Peter
P
Division of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL, UK.
Greenwood
John
J
Division of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL, UK.
D000284:Administration, Oral; D000818:Animals; D000069059:Atorvastatin; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology*; D002460:Cell Line; D002464:Cell Migration Inhibition; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D008148:Lovastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011758:Pyrroles / Q000008:administration & dosage; D051381:Rats; D011917:Rats, Inbred Lew; D012173:Retinitis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014605:Uveitis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology
D016207:Cytokines; D006131:Growth Inhibitors; D006538:Heptanoic Acids; D007166:Immunosuppressive Agents; D011758:Pyrroles; D008148:Lovastatin; D000069059:Atorvastatin