Structural and Functional Characterization of HQL-79, an Orally Selective Inhibitor of Human Hematopoietic Prostaglandin D Synthase

Aritake, Kosuke; Kado, Yuji; Inoue, Tsuyoshi; Miyano, Masashi; Urade, Yoshihiro

doi:10.1074/jbc.m506431200

Cited by 98 publications

(113 citation statements)

References 45 publications

Supporting

Mentioning

104

Contrasting

Unclassified

Order By: Relevance

“…When we inhibited HPGDS in mice with the small molecule compound HQL79 (ref. 31), renal excretion of the PGD 2 metabolite tetranor PGDM was reduced confirming the efficacy of HQL79 as a HPGDS inhibitor (Fig. 7d).…”

Section: Hca 2 Mediates the Neuroprotective Effect Of Ketogenic Dietsupporting

confidence: 50%

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

et al. 2014

View full text Add to dashboard Cite

The ketone body b-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA 2 , GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2 À / À mice. We further demonstrate that nicotinic acid, a clinically used HCA 2 agonist, reduces infarct size via a HCA 2 -mediated mechanism, and that noninflammatory Ly-6C Lo monocytes and/or macrophages infiltrating the ischemic brain also express HCA 2 . Using cell ablation and chimeric mice, we demonstrate that HCA 2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA 2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD 2 production by COX1 and the haematopoietic PGD 2 synthase. Our data suggest that HCA 2 activation by dietary or pharmacological means instructs Ly-6C Lo monocytes and/or macrophages to deliver a neuroprotective signal to the brain.

show abstract

Section: Hca 2 Mediates the Neuroprotective Effect Of Ketogenic Dietsupporting

confidence: 50%

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

et al. 2014

View full text Add to dashboard Cite

show abstract

“…7A). We then activated HMC-1 cells with A23187, a calcium ionophore (42), in the presence or absence of HQL-79, a specific inhibitor of H-PGDS (44,45), and determined PGD 2 production. Fig.…”

Section: Dp1 Activation Boosts Intracellular Camp To Increase Ha By Omentioning

confidence: 99%

Mast Cell-derived Prostaglandin D2 Controls Hyaluronan Synthesis in Human Orbital Fibroblasts via DP1 Activation

Guo

Baglole

O’Loughlin

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Thyroid eye disease (TED) is a debilitating disorder characterized by the accumulation of adipocytes and hyaluronan (HA).Production of HA by fibroblasts leads to remarkable increases in tissue volume and to the anterior displacement of the eyes. Prostaglandin D 2 (PGD 2 ), mainly produced by mast cells, promotes orbital fibroblast adipogenesis. The mechanism by which PGD 2 influences orbital fibroblasts and their synthesis of HA is poorly understood. We report here that mast cell-derived PGD 2 is a key factor that promotes HA biosynthesis by orbital fibroblasts. Primary orbital fibroblasts from TED patients were isolated and used to test the effects of PGD 2 , prostaglandin J 2 , as well as prostaglandin D receptor (DP) agonists and antagonists on HA synthesis. The expression of HA synthase (HAS), hyaluronidase, DP1, and DP2 mRNA levels was assessed by PCR. Small interfering RNAs against HAS1 or HAS2 were used to assess the importance

show abstract

“…In contrast, several other groups showed that PGD 2 signaling mediates proinflammatory responses. For example, administration of an H-PGDS inhibitor improved mouse airway inflammation (24). Furthermore, treatment with a CRTH2 agonist aggravated atopic dermatitis and asthma in mice, whereas intratracheal administration of PGD 2 promoted eosinophil migration in rats (25,26).…”

mentioning

confidence: 99%

Opposing Immunomodulatory Roles of Prostaglandin D2 during the Progression of Skin Inflammation

Sarashina

Tsubosaka

Omori

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The effects of PGD2 are extremely context dependent. It can have pro- or anti-inflammatory effects in clinically important pathological conditions. A greater mechanistic insight into the determinants of PGD2 activity during inflammation is thus required. In this study, we investigated the role of PGD2 in croton oil–induced dermatitis using transgenic (TG) mice overexpressing hematopoietic PGD synthase. Administration of croton oil caused tissue swelling and vascular leakage in the mouse ear. Compared with wild-type animals, TG mice produced more PGD2 and showed decreased inflammation in the early phase, but more severe manifestations during the late phase. Data obtained from bone marrow transplantation between wild-type and TG mice indicated that PGD2 produced by tissue resident cells in the TG mice attenuated early-phase inflammation, whereas PGD2 produced from hematopoietic lineage cells exacerbated late-phase inflammation. There are two distinct PGD2 receptors: D-prostanoid receptor (DP) and chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2). In TG mice, treatment with a DP antagonist exacerbated inflammation in the early phase, whereas treatment with a CRTH2 antagonist attenuated inflammation during the late phase. In vitro experiments showed that DP agonism enhanced vascular endothelial barrier formation, whereas CRTH2 agonism stimulated neutrophil migration. Collectively, these results show that when hematopoietic PGD synthase is overexpressed, tissue resident cell–derived PGD2 suppresses skin inflammation via DP in the early phase, but hematopoietic lineage cell–derived PGD2 stimulates CRTH2 and promotes inflammation during the late phase. DP-mediated vascular barrier enhancement or CRTH2-mediated neutrophil activation may be responsible for these effects. Thus, PGD2 represents opposite roles in inflammation, depending on the disease phase in vivo.

show abstract

Structural and Functional Characterization of HQL-79, an Orally Selective Inhibitor of Human Hematopoietic Prostaglandin D Synthase

Cited by 98 publications

References 45 publications

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

Mast Cell-derived Prostaglandin D2 Controls Hyaluronan Synthesis in Human Orbital Fibroblasts via DP1 Activation

Opposing Immunomodulatory Roles of Prostaglandin D2 during the Progression of Skin Inflammation

Contact Info

Product

Resources

About