E prostanoid 2 (EP2)/EP4‐mediated suppression of antigen‐specific human T‐cell responses by prostaglandin E₂

Abstract

Summary Prostaglandin E2 (PGE2) 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 PGE2 on cytokine production is greatly influenced by external stimuli; however, it is unclear whether PGE2 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 PGE2 on antigen‐specific CD4+ 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). PGE2 significantly and dose‐dependently inhibited the proliferation and subsequent production of interleukin‐4 by Cry j 1‐specific TCLs and of interferon‐γ 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, PGE2 and EP2 receptor agonist significantly inhibited interleukin‐5 and interferon‐γ production by peripheral blood mononuclear cells in response to Cry j 1 and PPD stimulation, respectively. These results suggest that PGE2 suppresses both Th1‐ and Th2‐polarized antigen‐specific human T‐cell responses via a cAMP‐dependent EP2/EP4‐mediated pathway.

Prostaglandin E2 Stimulates Human Lung Carcinoma Cell Growth through Induction of Integrin-Linked Kinase: The Involvement of EP4 and Sp1

“…Similar or even higher doses of exogenous PGE 2 have been shown to suppress both Th1-and Th2-polarized antigen-specific human T-cell responses and reduce radiation-induced apoptosis in human colon cancer cells (21,22). The effect of PGE 2 has been attributed to its known capacity to bind to its four G proteincoupled receptors (5,6).…”

TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells

“…PGE 2 exhibits a vast and diverse range of effects on the immune system, including the inhibition of proliferation 11,17 and the induction of apoptosis. [18][19][20][21] Interestingly, one of the mechanisms described to mediate PGE 2 -mediated apoptosis is the upregulation of CD95L.…”

The Prostanoid EP4 Receptor and Its Signaling Pathway

“…Messenger RNAs for EP2, EP3, and EP4, but not EP1, were detected in antigen-specific CD4+ human T cells (Okano et al, 2006). A recent study demonstrated that CD46 activation induced EP4 expression and caused a decrease in the IL-10/IFN-g ratio in T cells, and that an EP4 antagonist reversed this effect on cytokine production after CD46 stimulation (Kickler et al, 2012).…”