Stable prostacyclin analogues can signal through cell surface IP receptors or by ligand binding to nuclear peroxisome proliferator-activated receptors. (PPARs). So far these agents have been reported to activate PPAR alpha and PPAR delta but not PPAR gamma. Given PPAR gamma agonists and prostacyclin analogues both inhibit cell proliferation, we postulated that the IP receptor might elicit PPAR gamma activation. Using a dual luciferase reporter gene assay in HEK-293 cells stably expressing the IP receptor or empty vector, we found that prostacyclin analogues only activated PPAR gamma in the presence of the IP receptor. Moreover, the novel IP receptor antagonist, RO1138452, but not inhibitors of the cyclic AMP pathway, prevented activation. Likewise, the anti-proliferative effects of treprostinil observed in IP receptor expressing cells, were partially inhibited by the PPAR gamma antagonist, GW9662. We conclude that PPAR gamma is activated through the IP receptor via a cyclic AMP-independent mechanism and contributes to the anti-growth effects of prostacyclin analogues. (c) 2007 Elsevier Inc. All rights reserved.