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 uveiti s induced by immunization with uveal melanin protein. Fas and FasL enhancem ent is reported in rats with EMIU. Tricyclodecan-9-yl-xanthogenate (D609), a specific inhibitor of phosphatidylcholine-specific phospholipase C, inhib its inducible nitric oxide synthase (iNOS) induction. In two independent ex periments, 35 Lewis rats with EMIU received either D609 or PBS daily. The e yes and draining lymph nodes were collected for histology, analyses of nitr ite, peroxide, and superoxide dismutase, Fas and FasL immunochemistry, in s itu 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 a nd lower expressions of iNOS mRNA were found in D609-treated, as compared t o 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 i n 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 previo usly inhibited by NO along with other anti-inflammatory effects. (C) 1999 A cademic Press.