15-Deoxy-Δ12,14-prostaglandin J2

Abstract

Prostaglandin D 2 (PGD 2 ), a major cyclooxygenase product in a variety of tissues, readily undergoes dehydration to yield the cyclopentenone-type PGs of the J 2 series, such as 15-deoxy-⌬ 12,14 -PGJ 2 (15d-PGJ 2 ), which have been suggested to exert anti-inflammatory effects in vivo. Meanwhile, the mechanism of these effects is not well understood and the natural site and the extent of its production in vivo remain unclear. In the present study, we raised a monoclonal antibody specific to 15d-PGJ 2 and determined its production in inflammationrelated events. The monoclonal antibody (mAb11G2) was raised against the 15d-PGJ 2 -keyhole limpet hemocyanin conjugate and was found to recognize free 15d-PGJ 2 specifically. The presence of 15d-PGJ 2 in vivo was immunohistochemically verified in the cytoplasm of most of the foamy macrophages in human atherosclerotic plaques. In addition, the immunostaining of lipopolysaccharide-stimulated RAW264.7 macrophages with mAb11G2 demonstrated an enhanced intracellular accumulation of 15d-PGJ 2 , suggesting that the PGD 2 metabolic pathway, generating the anti-inflammatory PGs, is indeed utilized in the cells during inflammation. The activation of macrophages also resulted in the extracellular production of PGD 2 , which was associated with a significant increase in the extracellular 15d-PGJ 2 levels, and the extracellular 15d-PGJ 2 production was reproduced by incubating PGD 2 in a cell-free medium and in phosphate-buffered saline. Moreover, using a chiral high performance liquid chromatography method for separation of PGD 2 metabolites, we established a novel metabolic pathway, in which PGD 2 is converted to 15d-PGJ 2 via an albumin-independent mechanism.The prostaglandins (PGs) 1 are a family of structurally related molecules that are produced by cells in response to a variety of extrinsic stimuli and regulate cellular growth, differentiation, and homeostasis (1, 2). PGs are derived from fatty acids, primarily arachidonate, which are released from membrane phospholipids by the action of phospholipases. Arachidonate is first converted to an unstable endoperoxide intermediate by cyclooxygenases and subsequently converted to one of several related products, including PGD 2 , PGE 2 , PGF 2␣ , prostacyclin (PGI 2 ), and thromboxane A 2 , through the action of specific PG synthetases. PGD 2 , among them, is a major cyclooxygenase (COX) product in a variety of tissues and cells and has marked effects on a number of biological processes, including platelet aggregation, relaxation of vascular and nonvascular smooth muscles, and nerve cell functions (3). The PGs are physiologically present in body fluids in picomolar-to-nanomolar concentrations (4); however, arachidonate metabolism is highly increased under several pathological conditions, including hyperthermia, infection, and inflammation (5), and local PG concentrations in the micromolar range have been detected at sites of acute inflammation (6). In vitro, PGD 2 spontaneously converts into the cyclopentenone PGs of the J series, s...

α,β-Unsaturated Ketone Is a Core Moiety of Natural Ligands for Covalent Binding to Peroxisome Proliferator-activated Receptor γ

“…In atherosclerosis, macrophages play important roles in which oxidized low density lipoprotein accumulates as a major source of oxidized lipid (7). Under inflammatory conditions, macrophages express not only cyclooxygease-2 and 12/15-lipoxygenase, to produce prostaglandins and leukotrienes, respectively (31,32), but also nitric-oxide synthase to generate nitric oxide, another potent oxidative agent (33). In addition, expressions of prostaglandin transporter and 15-hydroxyprostaglandin dehydrogenase, both of which are involved in prostaglandin metabolism to form 15-keto-protstaglandins (34,35), were modulated during lipopolysaccharide-induced fever (36).…”

Formation of Highly Reactive A-ring and J-ring Isoprostane-like Compounds (A4/J4-neuroprostanes) in Vivo from Docosahexaenoic Acid

“…On the other hand, at concentrations in the nanomolar range, A-and J-series PGs induce proliferation (16 -18). One limitation of the studies reported to date with cyclopentenone PGs is that there is marked paucity of evidence that they are formed in vivo (19,20).…”

Molecular Basis for the Direct Inhibition of AP-1 DNA Binding by 15-Deoxy-Δ12,14-prostaglandin J2

“…cyPG have been detected in situations associated with an increase in cyclooxygenase-2 expression and PG production, such as acute and chronic inflammatory conditions (2)(3)(4). In addition, generation of cyPG has been reported in several experimental models, such as activated macrophages and mesangial cells (3,5). cyPG have received considerable attention during the past decade due to their action as antiproliferative agents and inducers of apoptosis in a variety of normal and cancer cell types (6,7).…”

“…Dehydration of PGD 2 gives rise to PGJ 2 and 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), whereas PGE 2 is converted into PGA 2 (1). cyPG have been detected in situations associated with an increase in cyclooxygenase-2 expression and PG production, such as acute and chronic inflammatory conditions (2)(3)(4). In addition, generation of cyPG has been reported in several experimental models, such as activated macrophages and mesangial cells (3,5).…”