Leukotriene E4 activates human Th2 cells for exaggerated pro-inflammatory cytokine production in response to PGD2 Note: Prostaglandin D2 ( PGD2) is one of the substances released by mast cells. Abstract PGD2 exerts a number of pro-inflammatory responses through a high affinity interaction with chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and has been detected at high concentrations at sites of allergic inflammation. Since cysteinyl leukotrienes (cysLTs) are also produced during the allergic response we investigated the possibility that cysLTs may modulate the response of human Th2 cells to PGD2. PGD2 induced concentration-dependent Th2 cytokine production in the absence of TCR stimulation. Leukotrienes D4 (LTD4) and E4 (LTE4) also stimulated the cytokine production but were much less active than PGD2. However, when combined with PGD2, cysLTs caused a greater than additive enhancement of the response, with LTE4 being most effective in activating Th2 cells. LTE4 enhanced calcium mobilisation in response to PGD2 in Th2 cells without affecting endogenous PGD2 production or CRTH2 receptor expression. The effect of LTE4 was inhibited by montelukast but not by the P2Y12 antagonistmethylthioadenosine 5′-monophosphate. The enhancing effect was also evident with endogenous cysLTs produced from immunologically activated mast cells since inhibition of cysLT action by montelukast or cysLT sythesis by MK886, an inhibitor of 5-LO-activating protein, reduced the response of Th2 cells to the levels produced by PGD2 alone. These findings reveal that cysLTs, in particular LTE4, have a significant pro-inflammatory impact on T cells and demonstrate their effects on Th2 cells are mediated by a montelukast-sensitive receptor.