Prostaglandin reductase 2 (PTGR2) catalyzes an NADPH-dependent reduction of the conjugated alpha, beta-unsaturated double bond of 15-keto-PGE(2), a key step in terminal inactivation of prostaglandins and suppression of PPAR gamma-mediated adipocyte differentiation. Selective inhibition of PTGR2 may contribute to the improvement of insulin sensitivity with fewer side effects. PTGR2 belongs to the medium-chain dehydrogenase/reductase superfamily.15-keto-PGE2 is a prostaglandin E2 (PGE2) metabolite, whose further processing is catalyzed by PTGR2. Disruption of the Ptgr2 gene in mice improves the survival rate under both LPS- and cecum ligation/puncture (CLP)-induced experimental sepsis. Knockdown of PTGR2 showed significant accumulation of intracellular 15k-PGE2 in activated macrophages. Both PTGR2 knockdown and exogenous treatment with 15k-PGE2 resulted in reduced pro-inflammatory cytokines production in LPS-stimulated RAW264.7 cells or bone marrow-derived macrophages (BMDM)[2]. In vitro analyses showed that silencing of PTGR2 expression enhanced ROS production, suppressed pancreatic cell proliferation, and promoted cell death through increasing 15-keto-PGE2. Mechanistically, silencing of PTGR2 or addition of 15-keto-PGE2 suppressed the expressions of solute carrier family 7 member 11 (xCT) and cystathionine gamma-lyase (CTH), two important providers of intracellular cysteine for the generation of glutathione (GSH), which is widely accepted as the first-line antioxidative defense. The oxidative stress-mediated cell death after silencing of PTGR2 or addition of 15-keto-PGE2 was further abolished after restoring intracellular GSH concentrations and cysteine supply by N-acetyl-L-cysteine and 2-Mercaptomethanol[3]. Normal monocytes in vitro increased migration and up-regulated CD16, RAP1GAP, IL-10, IL-8, MMP9 and down-regulated PTGR2 in response to leukemic cells or conditioned media[4].
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