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Novel Function of CRTH2 in Preventing Apoptosis of Human Th2 Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway

Oxagen Ltd., Abingdon, United Kingdom

It is now well established that interaction of PGD₂ with chemoattractant receptor- homologous molecule expressed on Th2 cells (CRTH2) promotes chemotaxis and proinflammatory cytokine production by Th2 lymphocytes. In this study we show a novel function of CRTH2 in mediating an inhibitory effect of PGD₂ on the apoptosis of human Th2 cells induced by cytokine deprivation. This effect was mimicked by the selective CRTH2 agonist 13,14-dihydro-15-keto-PGD₂, inhibited by the CRTH2 antagonists ramatroban and TM30089, and not observed in CRTH2-negative T cells. D prostanoid receptor 1 (DP₁) or the thromboxane-like prostanoid (TP) receptor did not play a role in mediating the effects of PGD₂ on the apoptosis of Th2 cells because neither the DP₁ antagonist BW868C nor the TP antagonist SQ29548 had any effect on the antiapoptotic effect of PGD₂. Apoptosis of Th2 cells induced by Fas ligation was not suppressed by treatment with PGD₂, illustrating that activation of CRTH2 only inhibits apoptosis induced by cytokine deprivation. Treatment with PGD₂ induced phosphorylation of Akt and BAD, prevented release of cytochrome c from mitochondria, and suppressed cleavage of caspase-3 and poly(ADP-ribose) polymerase in Th2 cells deprived of IL-2. The PI3K inhibitor LY294002 blocked the effect of PGD₂ both on the signaling events and on the apoptotic death of Th2 cells. These data suggest that in addition to promoting the recruitment and activation of Th2 cells, PGD₂ may also impede the resolution of allergic inflammation through inhibiting apoptosis of Th2 cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Luzheng Xue, Oxagen Ltd., 91 Milton Park, Abingdon, Oxon OX14 4RY, U.K. E-mail address: l.xue{at}oxagen.co.uk

² Abbreviations used in this paper: DP, D prostanoid receptor; BAF, t-butoxycarbonyl-Asp-fluoromethyl ketone; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; cyt c, cytochrome c; DK-PGD₂, 13,14-dihydro-15-keto-PGD₂; FasL, Fas ligand; PARP, poly(ADP-ribose) polymerase; PI, propidium iodide; TP, thromboxane-like prostanoid receptor; Treg, regulatory T cell; Z-IETD, N-benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethyl ketone; Z-VAD, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone.