Induction of human thioredoxin in cultured human retinal pigment epithelial cells through cyclic AMP-dependent pathway; Involvement in the cytoprotective activity of prostaglandin E-1

Human thioredoxin is one of the oxidative stress-inducible proteins and has a protective function against oxidant-induced injury. To evaluate the possible involvement of thioredoxin in the cytoprotective function of prostaglandin E-1, we analysed the effect of prostaglandin E, on cellular injury by hydrogen peroxide and intracellular thioredoxin induction. Cellular survival of human retinal pigment epithelial cell line, established from normal retinal pigment epithelial cells, following exposure to hydrogen peroxide was markedly improved by pretreatment of 1 mu M prostaglandin E-1. Thioredoxin expression was augmented in a dose-dependent manner when retinal pigment epithelial cells were pretreated with 10 nM-1 mu M prostaglandin E-1 1 hr before the exposure to hydrogen peroxide. Intracellular cyclic AMP level was elevated by Prostaglandin E-1 when the cells were simultaneously exposed to hydrogen peroxide. Forskolin, an activator of adenylate cyclase, and dibutylyl cAMP, a cyclic AMP analog, could also induce thioredoxin and extend survival of retinal pigment epithelial cells. On the other hand, thioredoxin induction and cellular protection by prostaglandin E-1 was blocked by Rp diastereoisomer of cyclic adenosine 3', 5', monophosphorothioate, a competitive inhibitor of cyclic AMP dependent protein kinase. Thioredoxin induction was augmented significantly by pretreatment with prostaglandin I-2, a Stimulator of cyclic AMP dependent signal pathway, while treatment with prostaglandin F-2x, a stimulator of inositol phosphate-dependent signal pathway, failed to enhance thioredoxin. These findings indicate that prostaglandin E-1 has a cytoprotective activity against oxidative injury, partly through thioredoxin induction via cyclic AMP dependent pathway. (C) 1997 Academic Press Limited.