E prostanoid 2 (EP2)-EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E sub(2)

Prostaglandin E sub(2) (PGE sub(2)) is a lipid mediator that displays important immunomodulatory properties, such as polarization of cytokine production by T cells. Recent investigations have revealed that the effect of PGE sub(2) on cytokine production is greatly influenced by external stimuli; however, it is unclear whether PGE sub(2) plays a significant role in major histocompatibility complex-mediated antigen-specific T-cell responses via binding to one of four subtypes of E prostanoid (EP) receptor alone or in combination. In the present study, we sought to determine the effect of PGE sub(2) on antigen-specific CD4 super(+) T-cell responses in humans, especially in terms of receptor specificity. We used purified protein derivative (PPD) and Cry j 1 as T helper type 1 (Th1) and Th2-inducing antigens, respectively. We generated several different Cry j 1- and PPD-specific T-cell lines (TCLs). PGE sub(2) significantly and dose-dependently inhibited the proliferation and subsequent production of interleukin-4 by Cry j 1-specific TCLs and of interferon- gamma by PPD-specific TCLs upon antigen stimulation. Administration of EP2 receptor agonist and EP4 receptor agonist suppressed these responses in an adenylate cyclase-dependent manner, while EP1 and EP3 receptor agonists did not. Messenger RNA for EP2, EP3 and EP4, but not EP1, receptors were detected in Cry j 1- and PPD-specific TCLs, and no differences in EP receptor expression were observed between them. Furthermore, PGE sub(2) and EP2 receptor agonist significantly inhibited interleukin-5 and interferon- gamma production by peripheral blood mononuclear cells in response to Cry j 1 and PPD stimulation, respectively. These results suggest that PGE sub(2) suppresses both Th1- and Th2-polarized antigen-specific human T-cell responses via a cAMP-dependent EP2-EP4-mediated pathway.