SPECIFIC SUPPRESSION BY PROSTAGLANDIN-E(2) OF ACTIVATION-INDUCED APOPTOSIS OF HUMAN CD4(-LYMPHOBLASTS()CD8(+) T)

Receptors (Rs) for prostaglandin E(2) (PGE(2)) of the EP(2) subtype ar e expressed at high levels in rodent and human thymuses, with preferen tial localization on immature thymocytes. Human cultured lymphoblasts of the Tsup-1 line express CD4 and CD8 but on ly a low level of CD3, t ypical of immature thymocytes, and bear EP(2)-type Rs for PGE(2) that were identified by binding of [H-3]PGE(2) and Ab to recombinant EP(2)R s, and by cAMP responses to PGE(2). PGE(2) protected Tsup-1 cells from apoptosis initiated by diverse stimuli, including mitogenic lectins a nd anti-Fas or anti-CD3 plus anti-CD28 Abs, but not ionomycin, as asse ssed by suppression of both fragmentation of [H-3]thymidine-labeled DN A and appearance of free 3'-OH ends of cleaved DNA. An EP(2)R-selectiv e synthetic agonist also significantly suppressed lectin-induced apopt osis of Tsup-1 cells. Phosphodiesterase inhibition synergistically enh anced PGE(2)-induced increases in cAMP and decreases in apoptosis in p arallel, which suggests that the EP(2)R-specific protective effect of PGE(2) is mediated predominantly by cAMP suppression of apoptosis. Dib utyrylcyclic AMP alone protected Tsup-1 cells against lectin-induced a poptosis, but the maximal effect was less than that for PGE(2). The th romboxane A(2) mimetic U46619 initiated apoptosis of Tsup-1 cells that was suppressed significantly by PGE(2). Immune negative selection of immature thymocytes thus may be regulated by opposing effects of endog enous eicosanoids that include destruction by thromboxane A(2) and pro tection by PGE(2).