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Yoshihiro Urade - One of the best experts on this subject based on the ideXlab platform.
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l PGDS deficiency accelerated the development of naturally occurring age related osteoarthritis
Aging, 2020Co-Authors: Yassine Ouhaddi, Yoshihiro Urade, Mehdi Najar, Frederic Pare, Bertrand Lussier, Jeanpierre Pelletier, Johanne Martelpelletier, Mohamed Benderdour, Hassan FahmiAbstract:Osteoarthritis (OA) is the most common musculoskeletal disorder among the elderly. It is characterized by progressive cartilage degradation, synovial inflammation, subchondral bone remodeling and pain. Lipocalin prostaglandin D synthase (L-PGDS) is responsible for the biosynthesis of PGD2, which has been implicated in the regulation of inflammation and cartilage biology. This study aimed to evaluate the effect of L-PGDS deficiency on the development of naturally occurring age-related OA in mice. OA-like structural changes were assessed by histology, immunohistochemistry, and micro-computed tomography. Pain related behaviours were assessed using the von Frey and the open-field assays. L-PGDS deletion promoted cartilage degradation during aging, which was associated with enhanced expression of extracellular matrix degrading enzymes, matrix metalloprotease 13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), and their breakdown products, C1,2C, VDIPEN and NITEG. Moreover, L-PGDS deletion enhanced subchondral bone changes, but had no effect on its angiogenesis. Additionally, L-PGDS deletion increased mechanical sensitivity and reduced spontaneous locomotor activity. Finally, we showed that the expression of L-PGDS was elevated in aged mice. Together, these findings indicate an important role for L-PGDS in naturally occurring age-related OA. They also suggest that L-PGDS may constitute a new efficient therapeutic target in OA.
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lipocalin type prostaglandin d synthase levels increase in patients with narcolepsy and idiopathic hypersomnia
Sleep, 2020Co-Authors: Peipei Wang, Yoshihiro Urade, Kosuke Aritake, Xiaosong Dong, Long Zhao, Han Yan, Zhili Huang, Kingman P Strohl, Jun Zhang, Fang HanAbstract:Study objectives Excessive daytime sleepiness (EDS) is a frequent cause for consultation and a defining symptom of narcolepsy and idiopathic hypersomnia (IH). The associated mechanisms remain unclear. Lipocalin-type prostaglandin D synthase (LPGDS) is a plausible sleep-inducing candidate. This study is to compare cerebral spinal fluid (CSF) and serum LPGDS levels in patients group with hypersomnia of central origin, including those with narcolepsy type 1 (NT1) and type 2 (NT2) and IH, to those in healthy controls (Con). Methods Serum LPGDS, CSF LPGDS and CSF hypocretin-1(Hcrt-1) levels were measured by ELISA in 122 narcolepsy patients (106 NT1, and 16 NT2), 27 IH, and 51Con. Results LPGDS levels in CSF (p=0.02) and serum (p 0.05), except for slightly lower serum LPGDS in IH than in NT1(p=0.01). Serum L-PGDS correlated modestly and negatively to sleep latency on MSLT(r=-0.227, p=0.007) in hypersomnia subjects. Conclusions As a somnogen-producing enzyme, CSF/serum LPGDS may serve as a new biomarker for EDS of central origin and imply a common pathogenetic association, but would complement rather than replaces orexin markers.
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role of lipocalin type prostaglandin d synthase in experimental osteoarthritis
Arthritis & Rheumatism, 2020Co-Authors: Mehdi Najar, Yoshihiro Urade, Yassine Ouhaddi, Frederic Pare, Bertrand Lussier, Mohit Kapoor, Jeanpierre Pelletier, Johanne Martelpelletier, Mohamed Benderdour, Hassan FahmiAbstract:OBJECTIVE Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the formation of prostaglandin D2 (PGD2 ), which has important roles in inflammation and cartilage metabolism. We undertook this study to investigate the role of L-PGDS in the pathogenesis of osteoarthritis (OA) using an experimental mouse model. METHODS Experimental OA was induced in wild-type (WT) and L-PGDS-deficient (L-PGDS-/- ) mice (n = 10 per genotype) by destabilization of the medial meniscus (DMM). Cartilage degradation was evaluated by histology. The expression of matrix metalloproteinase 13 (MMP-13) and ADAMTS-5 was assessed by immunohistochemistry. Bone changes were determined by micro-computed tomography. Cartilage explants from L-PGDS-/- and WT mice (n = 6 per genotype) were treated with interleukin-1α (IL-1α) ex vivo in order to evaluate proteoglycan degradation. Moreover, the effect of intraarticular injection of a recombinant adeno-associated virus type 2/5 (rAAV2/5) encoding L-PGDS on OA progression was evaluated in WT mice (n = 9 per group). RESULTS Compared to WT mice, L-PGDS-/- mice had exacerbated cartilage degradation and enhanced expression of MMP-13 and ADAMTS-5 (P < 0.05). Furthermore, L-PGDS-/- mice displayed increased synovitis and subchondral bone changes (P < 0.05). Cartilage explants from L-PGDS-/- mice showed enhanced proteoglycan degradation following treatment with IL-1α (P < 0.05). Intraarticular injection of rAAV2/5 encoding L-PGDS attenuated the severity of DMM-induced OA-like changes in WT mice (P < 0.05). The L-PGDS level was increased in OA tissues of WT mice (P < 0.05). CONCLUSION Collectively, these findings suggest a protective role of L-PGDS in OA, and therefore enhancing levels of L-PGDS may constitute a promising therapeutic strategy.
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L-PGDS-produced PGD2 in premature, but not in mature, adipocytes increases obesity and insulin resistance.
Scientific reports, 2019Co-Authors: Ko Fujimori, Kosuke Aritake, Michael Lazarus, Yo Oishi, Nanae Nagata, Toko Maehara, Yoshihiro UradeAbstract:Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is responsible for the production of PGD2 in adipocytes and is selectively induced by a high-fat diet (HFD) in adipose tissue. In this study, we investigated the effects of HFD on obesity and insulin resistance in two distinct types of adipose-specific L-PGDS gene knockout (KO) mice: fatty acid binding protein 4 (fabp4, aP2)-Cre/L-PGDS flox/flox and adiponectin (AdipoQ)-Cre/L-PGDS flox/flox mice. The L-PGDS gene was deleted in adipocytes in the premature stage of the former strain and after maturation of the latter strain. The L-PGDS expression and PGD2 production levels decreased in white adipose tissue (WAT) under HFD conditions only in the aP2-Cre/L-PGDS flox/flox mice, but were unchanged in the AdipoQ-Cre/L-PGDS flox/flox mice. When fed an HFD, aP2-Cre/L-PGDS flox/flox mice significantly reduced body weight gain, adipocyte size, and serum cholesterol and triglyceride levels. In WAT of the HFD-fed aP2-Cre/L-PGDS flox/flox mice, the expression levels of the adipogenic, lipogenic, and M1 macrophage marker genes were decreased, whereas those of the lipolytic and M2 macrophage marker genes were enhanced or unchanged. Insulin sensitivity was improved in the HFD-fed aP2-Cre/L-PGDS flox/flox mice. These results indicate that PGD2 produced by L-PGDS in premature adipocytes is involved in the regulation of body weight gain and insulin resistance under nutrient-dense conditions.
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the leptomeninges produce prostaglandin d2 involved in sleep regulation in mice
Frontiers in Cellular Neuroscience, 2018Co-Authors: Yoan Cherasse, Kosuke Aritake, Yo Oishi, Mahesh K Kaushik, Mustafa Korkutata, Yoshihiro UradeAbstract:Injection of nanomolar amounts of prostaglandin D2 (PGD2) into the rat brain has dose and time-dependent somnogenic effects, and the PGD2-induced sleep is indistinguishable from physiologic sleep. Sleep-inducing PGD2 is produced in the brain by lipocalin-type PGD2 synthase (LPGDS). Three potential intracranial sources of LPGDS to produce PGD2 have been identified: oligodendrocytes (OD), choroid plexus (CP), and leptomeninges (LM). We aimed at the identification of the site of synthesis of somnogenic PGD2 and therefore, generated a transgenic mouse line with the LPGDS gene amenable to conditional deletion using Cre recombinase (flox-LPGDS mouse). To identify the cell-type responsible for producing somnogenic PGD2, we engineered animals lacking LPGDS expression specifically in the oligodendrocytes (OD-LPGDS KO), choroid plexus (CP-LPGDS KO), or leptomeninges (LM-LPGDS KO). We measured prostaglandins and LPGDS concentrations together with PGD synthases (PGDS) activity in the brain of these mice. While the LPGDS amount and PGD synthase activity were drastically reduced in the OD- and LM-LPGDS KO mice, they were unchanged in the CP-LPGDS KO mice compared with control animals. We then recorded electroencephalograms, electromyograms, and locomotor activity to measure sleep in 10-week-old animals with specific knockdown of LPGDS in each of the three targets. Using selenium tetrachloride, a specific PGDS inhibitor, we demonstrated that sleep was inhibited in OD-LPGDS and CP-LPGDS KO mice, but not in the LM-LPGDS KO mice. We concluded that somnogenic PGD2 is produced primarily by the leptomeninges, and not the oligodendrocytes or choroid plexus.
Kosuke Aritake - One of the best experts on this subject based on the ideXlab platform.
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lipocalin type prostaglandin d synthase levels increase in patients with narcolepsy and idiopathic hypersomnia
Sleep, 2020Co-Authors: Peipei Wang, Yoshihiro Urade, Kosuke Aritake, Xiaosong Dong, Long Zhao, Han Yan, Zhili Huang, Kingman P Strohl, Jun Zhang, Fang HanAbstract:Study objectives Excessive daytime sleepiness (EDS) is a frequent cause for consultation and a defining symptom of narcolepsy and idiopathic hypersomnia (IH). The associated mechanisms remain unclear. Lipocalin-type prostaglandin D synthase (LPGDS) is a plausible sleep-inducing candidate. This study is to compare cerebral spinal fluid (CSF) and serum LPGDS levels in patients group with hypersomnia of central origin, including those with narcolepsy type 1 (NT1) and type 2 (NT2) and IH, to those in healthy controls (Con). Methods Serum LPGDS, CSF LPGDS and CSF hypocretin-1(Hcrt-1) levels were measured by ELISA in 122 narcolepsy patients (106 NT1, and 16 NT2), 27 IH, and 51Con. Results LPGDS levels in CSF (p=0.02) and serum (p 0.05), except for slightly lower serum LPGDS in IH than in NT1(p=0.01). Serum L-PGDS correlated modestly and negatively to sleep latency on MSLT(r=-0.227, p=0.007) in hypersomnia subjects. Conclusions As a somnogen-producing enzyme, CSF/serum LPGDS may serve as a new biomarker for EDS of central origin and imply a common pathogenetic association, but would complement rather than replaces orexin markers.
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Development of a Hematopoietic Prostaglandin D Synthase-Degradation Inducer
2020Co-Authors: Hidetomo Yokoo, Kosuke Aritake, Norihito Shibata, Miyako Naganuma, Kiyonaga Fujii, Takahito Ito, Mikihiko Naito, Yosuke DemizuAbstract:Although hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for treatment of a variety of diseases, including allergic diseases and Duchenne muscular dystrophy, no H-PGDS inhibitors have yet been approved for treatment of these diseases. Therefore, the development of novel agents having other mode of actions to modulate the activity of H-PGDS is required. In this study, a chimeric small molecule that degrades H-PGDS via the ubiquitin-proteasome system, PROTAC(H-PGDS)-1, was developed. PROTAC(H-PGDS)-1 is composed of two ligands, TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon). PROTAC(H-PGDS)-1 showed potent activity in the degradation of H-PGDS protein via the ubiquitin-proteasome system and in the suppression of prostaglandin D2 (PGD2) production. Notably, PROTAC(H-PGDS)-1 was slightly more effective in the suppression of PGD2 production than the known inhibitor, TFC-007. Thus, the H-PGDS degrader—PROTAC(H-PGDS)-1—is expected to be useful in biological research and clinical therapies.
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L-PGDS-produced PGD2 in premature, but not in mature, adipocytes increases obesity and insulin resistance.
Scientific reports, 2019Co-Authors: Ko Fujimori, Kosuke Aritake, Michael Lazarus, Yo Oishi, Nanae Nagata, Toko Maehara, Yoshihiro UradeAbstract:Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is responsible for the production of PGD2 in adipocytes and is selectively induced by a high-fat diet (HFD) in adipose tissue. In this study, we investigated the effects of HFD on obesity and insulin resistance in two distinct types of adipose-specific L-PGDS gene knockout (KO) mice: fatty acid binding protein 4 (fabp4, aP2)-Cre/L-PGDS flox/flox and adiponectin (AdipoQ)-Cre/L-PGDS flox/flox mice. The L-PGDS gene was deleted in adipocytes in the premature stage of the former strain and after maturation of the latter strain. The L-PGDS expression and PGD2 production levels decreased in white adipose tissue (WAT) under HFD conditions only in the aP2-Cre/L-PGDS flox/flox mice, but were unchanged in the AdipoQ-Cre/L-PGDS flox/flox mice. When fed an HFD, aP2-Cre/L-PGDS flox/flox mice significantly reduced body weight gain, adipocyte size, and serum cholesterol and triglyceride levels. In WAT of the HFD-fed aP2-Cre/L-PGDS flox/flox mice, the expression levels of the adipogenic, lipogenic, and M1 macrophage marker genes were decreased, whereas those of the lipolytic and M2 macrophage marker genes were enhanced or unchanged. Insulin sensitivity was improved in the HFD-fed aP2-Cre/L-PGDS flox/flox mice. These results indicate that PGD2 produced by L-PGDS in premature adipocytes is involved in the regulation of body weight gain and insulin resistance under nutrient-dense conditions.
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the leptomeninges produce prostaglandin d2 involved in sleep regulation in mice
Frontiers in Cellular Neuroscience, 2018Co-Authors: Yoan Cherasse, Kosuke Aritake, Yo Oishi, Mahesh K Kaushik, Mustafa Korkutata, Yoshihiro UradeAbstract:Injection of nanomolar amounts of prostaglandin D2 (PGD2) into the rat brain has dose and time-dependent somnogenic effects, and the PGD2-induced sleep is indistinguishable from physiologic sleep. Sleep-inducing PGD2 is produced in the brain by lipocalin-type PGD2 synthase (LPGDS). Three potential intracranial sources of LPGDS to produce PGD2 have been identified: oligodendrocytes (OD), choroid plexus (CP), and leptomeninges (LM). We aimed at the identification of the site of synthesis of somnogenic PGD2 and therefore, generated a transgenic mouse line with the LPGDS gene amenable to conditional deletion using Cre recombinase (flox-LPGDS mouse). To identify the cell-type responsible for producing somnogenic PGD2, we engineered animals lacking LPGDS expression specifically in the oligodendrocytes (OD-LPGDS KO), choroid plexus (CP-LPGDS KO), or leptomeninges (LM-LPGDS KO). We measured prostaglandins and LPGDS concentrations together with PGD synthases (PGDS) activity in the brain of these mice. While the LPGDS amount and PGD synthase activity were drastically reduced in the OD- and LM-LPGDS KO mice, they were unchanged in the CP-LPGDS KO mice compared with control animals. We then recorded electroencephalograms, electromyograms, and locomotor activity to measure sleep in 10-week-old animals with specific knockdown of LPGDS in each of the three targets. Using selenium tetrachloride, a specific PGDS inhibitor, we demonstrated that sleep was inhibited in OD-LPGDS and CP-LPGDS KO mice, but not in the LM-LPGDS KO mice. We concluded that somnogenic PGD2 is produced primarily by the leptomeninges, and not the oligodendrocytes or choroid plexus.
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Data_Sheet_1_The Leptomeninges Produce Prostaglandin D2 Involved in Sleep Regulation in Mice.docx
2018Co-Authors: Yoan Cherasse, Kosuke Aritake, Yo Oishi, Mahesh K Kaushik, Mustafa Korkutata, Yoshihiro UradeAbstract:Injection of nanomolar amounts of prostaglandin D2 (PGD2) into the rat brain has dose and time-dependent somnogenic effects, and the PGD2-induced sleep is indistinguishable from physiologic sleep. Sleep-inducing PGD2 is produced in the brain by lipocalin-type PGD2 synthase (LPGDS). Three potential intracranial sources of LPGDS have been identified: oligodendrocytes, choroid plexus, and leptomeninges. We aimed at the identification of the site of synthesis of somnogenic PGD2 and therefore, generated a transgenic mouse line with the LPGDS gene amenable to conditional deletion using Cre recombinase (flox-LPGDS mouse). To identify the cell type responsible for producing somnogenic PGD2, we engineered animals lacking LPGDS expression specifically in oligodendrocytes (OD-LPGDS KO), choroid plexus (CP-LPGDS KO), or leptomeninges (LM-LPGDS KO). We measured prostaglandins and LPGDS concentrations together with PGD synthase activity in the brain of these mice. While the LPGDS amount and PGD synthase activity were drastically reduced in the OD- and LM-LPGDS KO mice, they were unchanged in the CP-LPGDS KO mice compared with control animals. We then recorded electroencephalograms, electromyograms, and locomotor activity to measure sleep in 10-week-old mice with specific knockdown of LPGDS in each of the three targets. Using selenium tetrachloride, a specific PGDS inhibitor, we demonstrated that sleep is inhibited in OD-LPGDS and CP-LPGDS KO mice, but not in the LM-LPGDS KO mice. We concluded that somnogenic PGD2 is produced primarily by the leptomeninges, and not by oligodendrocytes or choroid plexus.
Hidero Kitasato - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of monosodium urate monohydrate crystal–induced acute inflammation by retrovirally transfected prostaglandin D synthase
Arthritis and rheumatism, 2003Co-Authors: Yousuke Murakami, Tohru Akahoshi, Izumi Hayashi, Hirahito Endo, Atsushi Hashimoto, Shizuka Kono, Hirobumi Kondo, Shinichi Kawai, Matsuhisa Inoue, Hidero KitasatoAbstract:Objective Hematopoietic prostaglandin D synthase (H-PGDS) is a key enzyme in the production of prostaglandin D and its J series metabolites. We evaluated the antiinflammatory effect of retrovirally transfected H-PGDS in order to investigate the role of H-PGDS in monosodium urate monohydrate (MSU) crystal–induced acute inflammation. Methods Expression of endogenous PGDS in a murine air-pouch model of MSU crystal–induced acute inflammation was determined by real-time polymerase chain reaction. H-PGDS complementary DNA (cDNA) was retrovirally transfected into C57BL/6J fibroblasts, and the cells were designated as C57-PGDS cells. Production of prostaglandins by C57-PGDS cells was measured by enzyme immunoassay. The effect of C57-PGDS cells on crystal-induced inflammation was investigated. Results Injection of the crystals caused a rapid decrease in H-PGDS expression by infiltrating cells and by the soft tissues around the air pouches. In contrast, expression of interleukin-1β (IL-1β) and macrophage inflammatory protein 2 (MIP-2) as well as cellular infiltration were significantly increased during the early stage of inflammation. C57-PGDS cells, but not control cells, produced an increased amount of PGD2 in vitro, but suppressed production of PGE2. Injection of C57-PGDS cells into air pouches inhibited cellular infiltration and MIP-2 and IL-1β expression. Conclusion In this murine air-pouch model of MSU crystal–induced inflammation, retrovirally transfected H-PGDS cDNA could reduce cellular infiltration, at least partly by inhibiting MIP-2 and IL-1β. These findings suggest that gene therapy with H-PGDS may be useful for treating inflammatory diseases.
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inhibition of monosodium urate monohydrate crystal induced acute inflammation by retrovirally transfected prostaglandin d synthase
Arthritis & Rheumatism, 2003Co-Authors: Yousuke Murakami, Tohru Akahoshi, Izumi Hayashi, Hirahito Endo, Atsushi Hashimoto, Shizuka Kono, Hirobumi Kondo, Shinichi Kawai, Matsuhisa Inoue, Hidero KitasatoAbstract:Objective Hematopoietic prostaglandin D synthase (H-PGDS) is a key enzyme in the production of prostaglandin D and its J series metabolites. We evaluated the antiinflammatory effect of retrovirally transfected H-PGDS in order to investigate the role of H-PGDS in monosodium urate monohydrate (MSU) crystal–induced acute inflammation. Methods Expression of endogenous PGDS in a murine air-pouch model of MSU crystal–induced acute inflammation was determined by real-time polymerase chain reaction. H-PGDS complementary DNA (cDNA) was retrovirally transfected into C57BL/6J fibroblasts, and the cells were designated as C57-PGDS cells. Production of prostaglandins by C57-PGDS cells was measured by enzyme immunoassay. The effect of C57-PGDS cells on crystal-induced inflammation was investigated. Results Injection of the crystals caused a rapid decrease in H-PGDS expression by infiltrating cells and by the soft tissues around the air pouches. In contrast, expression of interleukin-1β (IL-1β) and macrophage inflammatory protein 2 (MIP-2) as well as cellular infiltration were significantly increased during the early stage of inflammation. C57-PGDS cells, but not control cells, produced an increased amount of PGD2 in vitro, but suppressed production of PGE2. Injection of C57-PGDS cells into air pouches inhibited cellular infiltration and MIP-2 and IL-1β expression. Conclusion In this murine air-pouch model of MSU crystal–induced inflammation, retrovirally transfected H-PGDS cDNA could reduce cellular infiltration, at least partly by inhibiting MIP-2 and IL-1β. These findings suggest that gene therapy with H-PGDS may be useful for treating inflammatory diseases.
Yousuke Murakami - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of monosodium urate monohydrate crystal–induced acute inflammation by retrovirally transfected prostaglandin D synthase
Arthritis and rheumatism, 2003Co-Authors: Yousuke Murakami, Tohru Akahoshi, Izumi Hayashi, Hirahito Endo, Atsushi Hashimoto, Shizuka Kono, Hirobumi Kondo, Shinichi Kawai, Matsuhisa Inoue, Hidero KitasatoAbstract:Objective Hematopoietic prostaglandin D synthase (H-PGDS) is a key enzyme in the production of prostaglandin D and its J series metabolites. We evaluated the antiinflammatory effect of retrovirally transfected H-PGDS in order to investigate the role of H-PGDS in monosodium urate monohydrate (MSU) crystal–induced acute inflammation. Methods Expression of endogenous PGDS in a murine air-pouch model of MSU crystal–induced acute inflammation was determined by real-time polymerase chain reaction. H-PGDS complementary DNA (cDNA) was retrovirally transfected into C57BL/6J fibroblasts, and the cells were designated as C57-PGDS cells. Production of prostaglandins by C57-PGDS cells was measured by enzyme immunoassay. The effect of C57-PGDS cells on crystal-induced inflammation was investigated. Results Injection of the crystals caused a rapid decrease in H-PGDS expression by infiltrating cells and by the soft tissues around the air pouches. In contrast, expression of interleukin-1β (IL-1β) and macrophage inflammatory protein 2 (MIP-2) as well as cellular infiltration were significantly increased during the early stage of inflammation. C57-PGDS cells, but not control cells, produced an increased amount of PGD2 in vitro, but suppressed production of PGE2. Injection of C57-PGDS cells into air pouches inhibited cellular infiltration and MIP-2 and IL-1β expression. Conclusion In this murine air-pouch model of MSU crystal–induced inflammation, retrovirally transfected H-PGDS cDNA could reduce cellular infiltration, at least partly by inhibiting MIP-2 and IL-1β. These findings suggest that gene therapy with H-PGDS may be useful for treating inflammatory diseases.
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inhibition of monosodium urate monohydrate crystal induced acute inflammation by retrovirally transfected prostaglandin d synthase
Arthritis & Rheumatism, 2003Co-Authors: Yousuke Murakami, Tohru Akahoshi, Izumi Hayashi, Hirahito Endo, Atsushi Hashimoto, Shizuka Kono, Hirobumi Kondo, Shinichi Kawai, Matsuhisa Inoue, Hidero KitasatoAbstract:Objective Hematopoietic prostaglandin D synthase (H-PGDS) is a key enzyme in the production of prostaglandin D and its J series metabolites. We evaluated the antiinflammatory effect of retrovirally transfected H-PGDS in order to investigate the role of H-PGDS in monosodium urate monohydrate (MSU) crystal–induced acute inflammation. Methods Expression of endogenous PGDS in a murine air-pouch model of MSU crystal–induced acute inflammation was determined by real-time polymerase chain reaction. H-PGDS complementary DNA (cDNA) was retrovirally transfected into C57BL/6J fibroblasts, and the cells were designated as C57-PGDS cells. Production of prostaglandins by C57-PGDS cells was measured by enzyme immunoassay. The effect of C57-PGDS cells on crystal-induced inflammation was investigated. Results Injection of the crystals caused a rapid decrease in H-PGDS expression by infiltrating cells and by the soft tissues around the air pouches. In contrast, expression of interleukin-1β (IL-1β) and macrophage inflammatory protein 2 (MIP-2) as well as cellular infiltration were significantly increased during the early stage of inflammation. C57-PGDS cells, but not control cells, produced an increased amount of PGD2 in vitro, but suppressed production of PGE2. Injection of C57-PGDS cells into air pouches inhibited cellular infiltration and MIP-2 and IL-1β expression. Conclusion In this murine air-pouch model of MSU crystal–induced inflammation, retrovirally transfected H-PGDS cDNA could reduce cellular infiltration, at least partly by inhibiting MIP-2 and IL-1β. These findings suggest that gene therapy with H-PGDS may be useful for treating inflammatory diseases.
Takahisa Murata - One of the best experts on this subject based on the ideXlab platform.
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L-PGDS-derived PGD2 attenuates acute lung injury by enhancing endothelial barrier formation.
The Journal of pathology, 2019Co-Authors: Daiki Horikami, Nanae Nagata, Naoki Toya, Koji Kobayashi, Keisuke Omori, Takahisa MurataAbstract:Acute lung injury (ALI) is caused by various stimuli such as acid aspiration and infection, resulting in severe clinical outcomes with high mortality. Prostaglandin D2 (PGD2 ) is a lipid mediator produced in the lungs of patients with ALI. There are two prostaglandin D synthases (PGDS), namely, lipocalin-type PGDS (L-PGDS) and hematopoietic PGDS (H-PGDS). We previously reported the anti-inflammatory role of H-PGDS-derived PGD2 in an endotoxin-induced murine ALI model. Therefore, in this study, we investigated the role of L-PGDS-derived PGD2 in ALI in comparison to H-PGDS-derived PGD2 . Intratracheal administration of HCl caused lung inflammation accompanied by tissue edema and neutrophil accumulation in mouse lungs. The deficiency of both L-PGDS and H-PGDS exacerbated HCl-induced lung dysfunction to a similar extent. Furthermore, a detailed investigation revealed that L-PGDS-derived PGD2 inhibited lung edema, while H-PGDS-derived PGD2 inhibited neutrophil infiltration. Immunostaining showed that inflamed endothelial/epithelial cells express L-PGDS, while macrophages and neutrophils express H-PGDS. Hematopoietic reconstitution with WT bone marrow did not rescue the exacerbated lung edema in L-PGDS deficient mice, indicating the importance of nonhematopoietic endothelial/epithelial cell-expressing L-PGDS for protection against ALI. A modified Miles assay showed that L-PGDS deficiency accelerated vascular hyper-permeability in the inflamed lung, which was suppressed by the stimulation of D prostanoid (DP) receptor, a PGD2 receptor. In vitro, DP agonism enhanced the barrier function of endothelial cells but not epithelial cells. Taken together, our results suggest that in the HCl-induced murine ALI model PGD2 was produced locally by inflamed endothelial and epithelial L-PGDS and this enhanced the endothelial barrier through the DP receptor. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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lipocalin type prostaglandin d synthase derived pgd2 attenuates malignant properties of tumor endothelial cells
The Journal of Pathology, 2018Co-Authors: Keisuke Omori, Yoshihiro Urade, Kosuke Aritake, Teppei Morikawa, Akiko Kunita, Tatsuro Nakamura, Masashi Fukayama, Takahisa MurataAbstract:Endothelial cells (ECs) are a key component of the tumor microenvironment. They have abnormal characteristics compared to the ECs in normal tissues. Here, we found a marked increase in lipocalin-type prostaglandin D synthase (L-PGDS) mRNA (Ptgds) expression in ECs isolated from mouse melanoma. Immunostaining of mouse melanoma revealed expression of L-PGDS protein in the ECs. In situ hybridization also showed L-PGDS (PTGDS) mRNA expression in the ECs of human melanoma and oral squamous cell carcinoma. In vitro experiments showed that stimulation with tumor cell-derived IL-1 and TNF-α increased L-PGDS mRNA expression and its product prostaglandin D2 (PGD2 ) in human normal ECs. We also investigated the contribution of L-PGDS-PGD2 to tumor growth and vascularization. Systemic or EC-specific deficiency of L-PGDS accelerated the growth of melanoma in mice, whereas treatment with an agonist of the PGD2 receptor, DP1 (BW245C, 0.1 mg/kg, injected intraperitoneally twice daily), attenuated it. Morphological and in vivo studies showed that endothelial L-PGDS deficiency resulted in functional changes of tumor ECs such as accelerated vascular hyperpermeability, angiogenesis, and endothelial-to-mesenchymal transition (EndMT) in tumors, which in turn reduced tumor cell apoptosis. These observations suggest that tumor cell-derived inflammatory cytokines increase L-PGDS expression and subsequent PGD2 production in the tumor ECs. This PGD2 acts as a negative regulator of the tumorigenic changes in tumor ECs. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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lipocalin type prostaglandin d synthase derived pgd2 attenuates malignant properties of endothelial cells in tumor
The Journal of Pathology, 2017Co-Authors: Keisuke Omori, Yoshihiro Urade, Kosuke Aritake, Teppei Morikawa, Akiko Kunita, Tatsuro Nakamura, Masashi Fukayama, Takahisa MurataAbstract:Endothelial cells (ECs) are a key component of the tumor microenvironment. They have abnormal characteristics compared to the ECs in normal tissues. Here, we found a marked increase in lipocalin-type prostaglandin D synthase (L-PGDS) mRNA (Ptgds) expression in ECs isolated from mouse melanoma. Immunostaining of mouse melanoma revealed expression of L-PGDS protein in the ECs. In situ hybridization also showed L-PGDS (PTGDS) mRNA expression in the ECs of human melanoma and oral squamous cell carcinoma. In vitro experiments showed that stimulation with tumor cell-derived IL-1 and TNF-α increased L-PGDS mRNA expression and its product prostaglandin D2 (PGD2) in human normal ECs. We also investigated the contribution of L-PGDS–PGD2 to tumor growth and vascularization. Systemic or EC-specific deficiency of L-PGDS accelerated the growth of melanoma in mice, whereas treatment with an agonist of the PGD2 receptor, DP1 (BW245C, 0.1 mg/kg, injected intraperitoneally twice daily), attenuated it. Morphological and in vivo studies showed that endothelial L-PGDS deficiency resulted in functional changes of tumor ECs such as accelerated vascular hyperpermeability, angiogenesis, and endothelial-to-mesenchymal transition (EndMT) in tumors, which in turn reduced tumor cell apoptosis. These observations suggest that tumor cell-derived inflammatory cytokines increase L-PGDS expression and subsequent PGD2 production in the tumor ECs. This PGD2 acts as a negative regulator of the tumorigenic changes in tumor ECs. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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prostaglandin d2 attenuates bleomycin induced lung inflammation and pulmonary fibrosis
PLOS ONE, 2016Co-Authors: Taiki Kida, Yoshihiro Urade, Kosuke Aritake, Keisuke Omori, Tatsuro Nakamura, Toko Maehara, Shinya Ayabe, Takahisa MurataAbstract:Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naive (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.
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mast cell derived prostaglandin d2 inhibits colitis and colitis associated colon cancer in mice
Cancer Research, 2014Co-Authors: Koichi Iwanaga, Yoshihiro Urade, Kosuke Aritake, Tatsuro Nakamura, Shingo Maeda, Masatoshi Hori, Hiroshi Ozaki, Takahisa MurataAbstract:Compared with prostaglandin E2, which has an established role in cancer, the role of the COX metabolite prostaglandin D2 (PGD2) in chronic inflammation leading to tumorigenesis is uncertain. In this study, we investigated the role of PGD2 in colitis and colitis-associated colon cancer (CAC) using genetically modified mice and an established model of inflammatory colon carcinogenesis. Systemic genetic deficiency in hematopoietic PGD synthase (H-PGDS) aggravated colitis and accelerated tumor formation in a manner associated with increased TNFα expression. Treatment with a TNFα receptor antagonist attenuated colitis regardless of genotype. Histologic analysis revealed that infiltrated mast cells strongly expressed H-PGDS in inflamed colons. Mast cell–specific H-PGDS deficiency also aggravated colitis and accelerated CAC. In contrast, treatment with a PGD2 receptor agonist inhibited colitis and CAC. Together, our results identified mast cell–derived PGD2 as an inhibitor of colitis and CAC, with implications for its potential use in preventing or treating colon cancer. Cancer Res; 74(11); 3011–9. ©2014 AACR.