Conjunctival Sac Fluid Contains Elevated Levels of Soluble TRAIL: Implications for the Anti-Tumoral Surveillance of the Anterior Surface of the Eye

Little is known on the ability of different epithelia to release soluble TNF-related apoptosis-inducing ligand (TRAIL) and the relevance of TRAIL secretion by epithelial cells is still incompletely understood. On these bases, we have measured the concentration of soluble TRAIL by ELISA in the conjunctival sac fluid. It was the highest ever detected in a biological fluid (mean value of 26,800 pg/ml), being approximately 20-fold greater than that found in human saliva and > 200-fold greater than that detected in human serum. On the other hand, osteoprotegerin, the soluble decoy receptor of TRAIL, was almost undetectable in the conjunctival sac fluid. Of note, the levels of soluble TRAIL measured in conjunctival sac fluid were in the range able to induce in vitro apoptosis of lymphoma cells. By in Situ immunohistochemistry, TRAIL protein expression was predominantly detected in the corneal epithelium and, to a less extent, in the conjunctival epithelium. By flow cytometry analysis, membrane-associated TRAIL was documented in isolated corneal epithelial cells obtained from patients undergoing photorefractive keratectomy (PRK). The key contribution provided by corneal epithelium to the production of soluble TRAIL was underscored in time-course experiments, in which a marked decrease of the levels of soluble TRAIL in the conjunctival sac fluid was demonstrated I day after PRK followed by a progressive recovery at days 5-30 after PRK. Taken together, our findings strongly support a major role of soluble TRAIL in protecting cornea and conjunctiva from tumor formation and/or invasion.