Inhibition of experimental melanin protein-induced uveitis (EMIU) by targeting nitric oxide via phosphatidylcholine-specific phospholipase C.
Experimental melanin protein-induced uveitis (EMIU) is an autoimmune uveitis induced by immunization with uveal melanin protein. Fas and FasL enhancement is reported in rats with EMIU. Tricyclodecan-9-yl-xanthogenate (D609), a specific inhibitor of phosphatidylcholine-specific phospholipase C, inhibits inducible nitric oxide synthase (iNOS) induction. In two independent experiments, 35 Lewis rats with EMIU received either D609 or PBS daily. The eyes and draining lymph nodes were collected for histology, analyses of nitrite, peroxide, and superoxide dismutase, Fas and FasL immunochemistry, in situ hybridization for iNOS mRNA and in situ apoptosis detection at the peak of the disease. Both experiments showed significant inhibition of EMIU by D609. Decreases in nitrite and peroxide, increase of superoxide dismutase and lower expressions of iNOS mRNA were found in D609-treated, as compared to PBS-treated eyes. There was mild enhancement of Fas and FasL in the eyes and lymph nodes of D609-injected animals. DNA fragmentation was increased in the lymph nodes of D609-treated rats. We conclude that iNOS activation is responsible for NO production in eyes with EMIU. The suppressive effect of D609 on EMIU may result from scavenging NO and activating apoptosis previously inhibited by NO along with other anti-inflammatory effects.
Matteson
D M
DM
National Eye Institute, Bethesda, Maryland 20892-1857, USA.
Shen
D F
DF
Chan
C C
CC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D015536:Down-Regulation; D004790:Enzyme Induction / Q000187:drug effects; D005136:Eye Proteins / Q000276:immunology; D053222:Fas Ligand Protein; D005260:Female; D008543:Melanins / Q000276:immunology; D008562:Membrane Glycoproteins / Q000302:isolation & purification; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D009636:Norbornanes; D051381:Rats; D011917:Rats, Inbred Lew; D013859:Thiocarbamates; D013871:Thiones / Q000627:therapeutic use*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*; D014602:Uvea / Q000473:pathology; D014605:Uveitis / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology
D001952:Bridged-Ring Compounds; D005136:Eye Proteins; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008543:Melanins; D008562:Membrane Glycoproteins; D009636:Norbornanes; D013859:Thiocarbamates; D013871:Thiones; D009569:Nitric Oxide; C046498:tricyclodecane-9-yl-xanthogenate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C