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Shuh Narumiya - One of the best experts on this subject based on the ideXlab platform.
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Prostaglandin E rEcEptor subtypE Ep3 in conjunctival EpithElium rEgulatEs latE phasE rEaction of ExpErimEntal allErgic conjunctivitis
The Journal of Allergy and Clinical Immunology, 2009Co-Authors: Shuh Narumiya, Toshiyuki Matsuoka, Mayumi Ueta, Shigeru KinoshitaAbstract:Background WE prEviously dEmonstratEd that thE Prostaglandin E 2 (PGE 2 )–EP3 pathway nEgativEly rEgulatEs allErgic rEactions in a murinE allErgic asthma modEl. ObjEctivEs WE invEstigatEd whEthEr thE PGE 2 -EP3 pathway also rEgulatEs thE dEvElopmEnt of murinE ExpErimEntal allErgic conjunctivitis (EAC). MEthods ThE ExprEssion of EP3 was ExaminEd by mEans of RT-PCR and immunohistochEmistry in wild-typE micE, as wEll as by mEans of 5-bromo-4-chloro-3-indolyl-β-D-galactopyranosidE staining in micE dEficiEnt in EP3 ( PtgEr3 −/− micE) carrying thE β-galactosidasE gEnE at thE EP3 gEnE locus. EAC was inducEd by immunization of micE with short ragwEEd pollEn (RW), followEd by challEngE with EyE drops of RW, and Eosinophil infiltration and Eotaxin-1 mRNA ExprEssion in thE conjunctiva wErE ExaminEd. MicE wErE also trEatEd with a topical application of an EP3-sElEctivE agonist during thE Elicitation phasE. QuantitativE RT-PCR was usEd to dEtEct ExprEssion of COXs and Prostaglandin E synthasEs, and ELISA was usEd to mEasurE PGE 2 production in thE EyElid. REsults EP3 was constitutivEly ExprEssEd in conjunctival EpithElium on thE ocular surfacE. PtgEr3 −/− micE dEmonstratEd significantly incrEasEd Eosinophil infiltration in conjunctiva aftEr RW challEngE comparEd with wild-typE micE. ConsistEntly, significantly highEr ExprEssion of Eotaxin-1 mRNA was obsErvEd in PtgEr3 −/− micE. ConvErsEly, trEatmEnt of wild-typE micE with an EP3-sElEctivE agonist rEsultEd in a significant dEcrEasE in Eosinophil infiltration, which was bluntEd in PtgEr3 −/− micE. ExprEssion of COX-2 and Prostaglandin E synthasEs was uprEgulatEd and PGE 2 contEnt was incrEasEd in thE EyElids aftEr RW challEngE. Conclusion ThEsE data suggEst that PGE 2 acts on EP3 in conjunctival EpithElium and downrEgulatEs thE progrEssion of EAC.
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Prostaglandin E rEcEptor Ep3 dEficiEncy modifiEs tumor outcomE in mousE two stagE skin carcinogEnEsis
Carcinogenesis, 2005Co-Authors: Yutaka Shoji, Tomohiro Kitamura, Takayuki Maruyama, Shuh Narumiya, Yukihiko Sugimoto, Mami Takahashi, Nobuo Takasuka, Naoko Niho, Hidetaka Sato, Takashi SugimuraAbstract:WE havE rEcEntly shown that thE Prostaglandin E(2) (PGE(2)) rEcEptor EP(3) plays an important rolE in supprEssion of colon cancEr cEll prolifEration and that its dEficiEncy EnhancEs latE stagE colon carcinogEnEsis. HErE wE ExaminEd thE EffEcts of EP(3)-dEficiEncy on two-stagE skin carcinogEnEsis. 7,12-DimEthylbEnz[a]anthracEnE (50 microg/200 microl of acEtonE) was thus appliEd to thE back skin of fEmalE EP(3)-knockout and wild-typE micE at 8 wEEks of agE, followEd by trEatmEnt with 12-O-tEtradEcanoylphorbol-13-acEtatE (5 microg/200 microl of acEtonE) twicE a wEEk for 25 wEEks. First tumor appEarancE was obsErvEd in EP(3)-knockout micE at wEEk 10, which was 3 wEEks latEr than in EP(3) wild-typE micE, and multiplicity obsErvEd at wEEk 11 was significantly lowEr in thE EP(3)-knockout casE. HowEvEr, histological Examination showEd that thE tumor incidEncE and multiplicity at wEEk 25 wErE not significantly changEd in knockout micE and wild-typE micE (incidEncE, 19/19 vErsus 23/24; multiplicity, 3.58 +/- 0.51 vErsus 3.17 +/- 0.63, rEspEctivEly). IntErEstingly, thErE wErE no squamous cEll carcinomas (SCCs) in thE EP(3)-knockout micE, whilE SCCs wErE obsErvEd in 3 out of 24 wild-typE micE. FurthErmorE, bEnign kEratoacanthomas only dEvElopEd in EP(3)-knockout micE (6/19 vErsus 0/24, P < 0.01). ThE rEsults suggEst that PGE(2) rEcEptor EP(3) signaling might contributE to dEvElopmEnt of SCCs in thE skin.
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Prostaglandin E rEcEptor EP1 controls impulsivE bEhavior undEr strEss
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Yoko Matsuoka, Fumitaka Ushikubi, Tomoyuki Furuyashiki, Kiyofumi Yamada, Taku Nagai, Haruhiko Bito, Yasuhiro R. Tanaka, Shiho Kitaoka, Toshitaka Nabeshima, Shuh NarumiyaAbstract:Animals undEr strEss takE adaptivE actions that may lEad to various typEs of bEhavioral disinhibition. Such bEhavioral disinhibition, whEn ExprEssEd ExcEssivEly and impulsivEly, can rEsult in harm in individuals and causE a problEm in our sociEty. WE now show that, undEr social or EnvironmEntal strEss, micE dEficiEnt in Prostaglandin E rEcEptor subtypE EP1 (PtgEr1-/-) manifEst bEhavioral disinhibition, including impulsivE aggrEssion with dEfEctivE social intEraction, impairEd cliff avoidancE, and an ExaggEratEd acoustic startlE rEsponsE. This phEnotypE was rEproducEd in wild-typE micE by administration of an EP1-sElEctivE antagonist, whErEas administration of an EP1-sElEctivE agonist supprEssEd ElEctric-shock-inducEd impulsivE aggrEssion. DopaminE turnovEr in thE frontal cortEx and striatum was incrEasEd in PtgEr1-/- micE, and administration of dopaminErgic antagonists corrEctEd thEir bEhavioral phEnotypE. ThEsE rEsults suggEst that Prostaglandin E2 acts through EP1 to control impulsivE bEhavior undEr strEss, a finding potEntially ExploitablE for dEvElopmEnt of drugs that attEnuatE impulsivE bEhavior in humans.
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SupprEssion of allErgic inflammation by thE Prostaglandin E rEcEptor subtypE EP3
Nature immunology, 2005Co-Authors: Tomonori Kunikata, Hana Yamane, Eri Segi, Toshiyuki Matsuoka, Yukihiko Sugimoto, Satoshi Tanaka, Hiroyuki Tanaka, Hiroichi Nagai, Atsushi Ichikawa, Shuh NarumiyaAbstract:Prostaglandins, including PGD(2) and PGE(2), arE producEd during allErgic rEactions. Although PGD(2) is an important mEdiator of allErgic rEsponsEs, aspirin-likE drugs that inhibit Prostaglandin synthEsis arE gEnErally inEffEctivE in allErgic disordErs, suggEsting that anothEr Prostaglandin-mEdiatEd pathway prEvEnts thE dEvElopmEnt of allErgic rEactions. HErE wE show that such a pathway may bE mEdiatEd by PGE(2) acting at thE Prostaglandin E rEcEptor EP3. MicE lacking EP3 dEvElopEd allErgic inflammation that was much morE pronouncEd than that in wild-typE micE or micE dEficiEnt in othEr Prostaglandin E rEcEptor subtypEs. ConvErsEly, an EP3-sElEctivE agonist supprEssEd thE inflammation. This supprEssion was EffEctivE whEn thE agonist was administErEd 3 h aftEr antigEn challEngE and was associatEd with inhibition of allErgy-rElatEd gEnE ExprEssion. Thus, thE PGE(2)-EP3 pathway is an important nEgativE modulator of allErgic rEactions.
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Prostaglandin E rEcEptor subtypE Ep1 dEficiEncy inhibits colon cancEr dEvElopmEnt
Carcinogenesis, 2004Co-Authors: Toshihiko Kawamori, Tomohiro Kitamura, Kouji Watanabe, Takayuki Maruyama, Shuh Narumiya, Naoaki Uchiya, Takashi Sugimura, Keiji WakabayashiAbstract:Prostaglandin E 2 ExErts its biological activity through binding to its mEmbranE rEcEptors, E-prostanoid (EP) rEcEptors 1-4 . Our prEvious finding that lack of EP 1 rEcEptor inhibits thE Early stagEs of colon carcinogEnEsis lEd us to invEstigatE whEthEr EP 1 rEcEptor dEficiEncy rEducEs colon cancEr dEvElopmEnt inducEd by azoxymEthanE (AOM) using EP 1 rEcEptor knockout micE. At 6 wEEks of agE 33 homozygous EP 1 -dEficiEnt (EP 1 -/- ) micE and 28 wild-typE (EP 1 +/+ ) micE wErE givEn i.p. AOM (10 mg/kg body wt) oncE a wEEk for 6 wEEks. At 56 wEEks of agE all animals wErE killEd and intEstinal tumors wErE ExaminEd. ThE rEsults clEarly indicatEd that lack of EP 1 rEcEptor significantly rEducEd colon cancEr incidEncE (27 vErsus 57%, P < 0.05) and multiplicity (0.30 vErsus 0.76, P < 0.05) as wEll as tumor volumE (12.2 vErsus 75.6 mm 3 , P < 0.05). In EP 1 -/- micE, silvEr stainEd nuclEolar organization rEgion protEin count as cEll prolifEration markEr was significantly rEducEd (1.35 vErsus 2.17, P < 0.001) and apoptosis was significantly incrEasEd (0.685 vErsus 0.077, P < 0.001) in colon tumors inducEd by AOM comparEd with thosE in EP 1 +/+ micE. WE confirmEd that EP 1 rEcEptor mRNA was ovErExprEssEd in colon cancErs of EP 1 +/+ micE using rEvErsE transcription-polymErasE chain rEaction. ThEsE rEsults providE strong EvidEncE that thE EP 1 rEcEptor is of major importancE for colon cancEr dEvElopmEnt and it could bE a nEw targEt for a mEchanism-basEd chEmoprEvEntion stratEgy against colon cancEr dEvElopmEnt.
Carrie L Randalla - One of the best experts on this subject based on the ideXlab platform.
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cocainE doEs not affEct prostacyclin thromboxanE or Prostaglandin E production in human umbilical vEins
Drug and Alcohol Dependence, 1996Co-Authors: Jocelynn L Cook, Carrie L RandallaAbstract:VasoactivE Prostaglandins havE bEEn rEportEd to mEdiatE umbilical/placEntal blood flow in humans. SincE it has bEEn suggEstEd that cocainE ExErts its tEratogEnic action via vasoconstriction and a corrEsponding rEduction in blood flow, it is rEasonablE to hypothEsizE that cocainE influEncEs thE vasoactivE Prostaglandins such that blood flow would bE affEctEd. ThE purposE of this study, thErEforE, was to dEtErminE thE EffEcts of cocainE on thE vasoactivE Prostaglandins prostacyclin, thromboxanE, and Prostaglandin E, using human umbilical vEins. Prostacyclin (PGI2), thromboxanE (TXA2), and Prostaglandin E (PGE) lEvEls wErE mEasurEd from human umbilical vEins collEctEd at tErm. ThE vEins wErE pErfusEd in a closEd systEm with EithEr a 50 μg/ml, a 100 μg/ml, a 200 μg/ml, or a 400 μg/ml cocainE solution for 60 min, and thE Prostaglandins wErE mEasurEd by radioimmunoassay of thEir stablE mEtabolitEs. Data wErE analyzEd by ANOVA, and post-hoc analysEs wErE pErformEd by FishEr's ProtEctEd LEast Significant DiffErEncE TEst. CocainE did not influEncE PGI2, TXA2, or PGE production (Ps > 0.05) in this sEriEs of studiEs. Thus, contraction of human umbilical vEssEls and dEcrEasEd blood flow in human umbilical vEssEls doEs not appEar to bE mEdiatEd by changEs in thE vasoactivE Prostaglandins.
Takayuki Maruyama - One of the best experts on this subject based on the ideXlab platform.
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Prostaglandin E rEcEptor Ep4 antagonist supprEssEs ostEolysis duE to bonE mEtastasis of mousE malignant mElanoma cElls
FEBS Letters, 2007Co-Authors: Morichika Takita, Takayuki Maruyama, Masaki Inada, Chisato MiyauraAbstract:WE ExaminEd thE EffEcts of Prostaglandin E (PGE) rEcEptor subtypE EP4 antagonist on bonE mEtastasis of cancEr to clarify PGE's rolE in bonE mEtastasis. MEtastatic rEgions wErE dEtEctEd in fEmurs accompanying sEvErE bonE loss in micE injEctEd with B16 malignant mElanoma cElls. Administration of EP4 antagonist rEstorEd thE bonE loss inducEd by B16 mElanoma. Adding B16 cElls inducEd ostEoclast formation in thE coculturE of bonE marrow cElls and ostEoblasts without any ExogEnous bonE-rEsorbing factor, and EP4 antagonist complEtEly supprEssEd thE ostEoclast formation inducEd by B16 cElls. ThErEforE, EP4 antagonist is a possiblE candidatE for thE thErapy of bonE mEtastasis of cancEr.
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Prostaglandin E rEcEptor Ep3 dEficiEncy modifiEs tumor outcomE in mousE two stagE skin carcinogEnEsis
Carcinogenesis, 2005Co-Authors: Yutaka Shoji, Tomohiro Kitamura, Takayuki Maruyama, Shuh Narumiya, Yukihiko Sugimoto, Mami Takahashi, Nobuo Takasuka, Naoko Niho, Hidetaka Sato, Takashi SugimuraAbstract:WE havE rEcEntly shown that thE Prostaglandin E(2) (PGE(2)) rEcEptor EP(3) plays an important rolE in supprEssion of colon cancEr cEll prolifEration and that its dEficiEncy EnhancEs latE stagE colon carcinogEnEsis. HErE wE ExaminEd thE EffEcts of EP(3)-dEficiEncy on two-stagE skin carcinogEnEsis. 7,12-DimEthylbEnz[a]anthracEnE (50 microg/200 microl of acEtonE) was thus appliEd to thE back skin of fEmalE EP(3)-knockout and wild-typE micE at 8 wEEks of agE, followEd by trEatmEnt with 12-O-tEtradEcanoylphorbol-13-acEtatE (5 microg/200 microl of acEtonE) twicE a wEEk for 25 wEEks. First tumor appEarancE was obsErvEd in EP(3)-knockout micE at wEEk 10, which was 3 wEEks latEr than in EP(3) wild-typE micE, and multiplicity obsErvEd at wEEk 11 was significantly lowEr in thE EP(3)-knockout casE. HowEvEr, histological Examination showEd that thE tumor incidEncE and multiplicity at wEEk 25 wErE not significantly changEd in knockout micE and wild-typE micE (incidEncE, 19/19 vErsus 23/24; multiplicity, 3.58 +/- 0.51 vErsus 3.17 +/- 0.63, rEspEctivEly). IntErEstingly, thErE wErE no squamous cEll carcinomas (SCCs) in thE EP(3)-knockout micE, whilE SCCs wErE obsErvEd in 3 out of 24 wild-typE micE. FurthErmorE, bEnign kEratoacanthomas only dEvElopEd in EP(3)-knockout micE (6/19 vErsus 0/24, P < 0.01). ThE rEsults suggEst that PGE(2) rEcEptor EP(3) signaling might contributE to dEvElopmEnt of SCCs in thE skin.
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Prostaglandin E rEcEptor subtypE Ep1 dEficiEncy inhibits colon cancEr dEvElopmEnt
Carcinogenesis, 2004Co-Authors: Toshihiko Kawamori, Tomohiro Kitamura, Kouji Watanabe, Takayuki Maruyama, Shuh Narumiya, Naoaki Uchiya, Takashi Sugimura, Keiji WakabayashiAbstract:Prostaglandin E 2 ExErts its biological activity through binding to its mEmbranE rEcEptors, E-prostanoid (EP) rEcEptors 1-4 . Our prEvious finding that lack of EP 1 rEcEptor inhibits thE Early stagEs of colon carcinogEnEsis lEd us to invEstigatE whEthEr EP 1 rEcEptor dEficiEncy rEducEs colon cancEr dEvElopmEnt inducEd by azoxymEthanE (AOM) using EP 1 rEcEptor knockout micE. At 6 wEEks of agE 33 homozygous EP 1 -dEficiEnt (EP 1 -/- ) micE and 28 wild-typE (EP 1 +/+ ) micE wErE givEn i.p. AOM (10 mg/kg body wt) oncE a wEEk for 6 wEEks. At 56 wEEks of agE all animals wErE killEd and intEstinal tumors wErE ExaminEd. ThE rEsults clEarly indicatEd that lack of EP 1 rEcEptor significantly rEducEd colon cancEr incidEncE (27 vErsus 57%, P < 0.05) and multiplicity (0.30 vErsus 0.76, P < 0.05) as wEll as tumor volumE (12.2 vErsus 75.6 mm 3 , P < 0.05). In EP 1 -/- micE, silvEr stainEd nuclEolar organization rEgion protEin count as cEll prolifEration markEr was significantly rEducEd (1.35 vErsus 2.17, P < 0.001) and apoptosis was significantly incrEasEd (0.685 vErsus 0.077, P < 0.001) in colon tumors inducEd by AOM comparEd with thosE in EP 1 +/+ micE. WE confirmEd that EP 1 rEcEptor mRNA was ovErExprEssEd in colon cancErs of EP 1 +/+ micE using rEvErsE transcription-polymErasE chain rEaction. ThEsE rEsults providE strong EvidEncE that thE EP 1 rEcEptor is of major importancE for colon cancEr dEvElopmEnt and it could bE a nEw targEt for a mEchanism-basEd chEmoprEvEntion stratEgy against colon cancEr dEvElopmEnt.
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CombinEd EffEcts of Prostaglandin E rEcEptor subtypE EP1 and subtypE EP4 antagonists on intEstinal tumorigEnEsis in adEnomatous polyposis coli gEnE knockout micE.
Cancer science, 2003Co-Authors: Tomohiro Kitamura, Kousuke Tani, Michiyoshi Kobayashi, Shuichi Ohuchida, Takayuki Maruyama, Kaoru Kobayashi, Takashi Sugimura, Masaki Itoh, Tetsuo Noda, Keiji WakabayashiAbstract:PrEvious studiEs havE shown that Prostaglandin E(2) (PGE(2)) is involvEd in intEstinal carcinogEnEsis through its binding to thE PGE(2) rEcEptor subtypEs EP(1) and EP(4) and activation of downstrEam pathways. ONO-8711 and ONO-AE2-227, Prostaglandin E rEcEptor subtypE EP(1)- and EP(4)-sElEctivE antagonists, rEspEctivEly, arE known to supprEss formation of intEstinal polyps in adEnomatous polyposis coli gEnE-dEficiEnt micE. ThE prEsEnt study was dEsignEd to invEstigatE thE combinEd EffEcts of EP(1) and EP(4) antagonists on spontanEous polyp formation in APC1309 micE in ordEr to dEtErminE thE contribution of Each rEcEptor to intEstinal tumorigEnEsis. APC1309 micE wErE trEatEd with 400 ppm of ONO-8711 alonE, 400 ppm of ONO-AE2-227 alonE or both in combination in thE diEt for 6 wEEks. ThE mEan arEa of polyps found in thE intEstinE, calculatEd as thE longEr diamEtEr x thE shortEr diamEtEr x pi, was rEducEd by 12%, 43% (P < 0.01) and 56% (P < 0.01) of thE mEan control valuE (8.8 mm(2)) in thE ONO-8711 alonE, ONO-AE2-227 alonE and combination trEatmEnt groups, rEspEctivEly, suggEsting clEar additivE EffEcts of thE combination. ThE samE additivE tEndEncy for supprEssion was also obsErvEd with rEspEct to thE numbErs of polyps in thE intEstinE. Polyp sizE rEduction was morE rEmarkablE with thE EP(4) antagonist, whilE thE numbEr rEduction was morE pronouncEd with thE EP(1) antagonist. Our rEsults indicatE that EP(1) and EP(4) may havE sEparatE intrinsic rolEs and, to somE ExtEnt, contributE to polyp formation indEpEndEntly. Thus, combination trEatmEnt has potEntial for thE chEmoprEvEntion of colon carcinogEnEsis.
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Inhibitory EffEct of a Prostaglandin E rEcEptor subtypE EP1 sElEctivE antagonist, ONO-8713, on dEvElopmEnt of azoxymEthanE-inducEd abErrant crypt foci in micE
Cancer letters, 2000Co-Authors: Kouji Watanabe, Seiichi Nakatsugi, Toshihisa Ohta, Toshihiko Kawamori, Shuichi Ohuchida, Kigen Kondo, Takayuki Maruyama, Shuh Narumiya, Hiroshi Yamamoto, Takashi SugimuraAbstract:Abstract WE prEviously rEportEd that Prostaglandin E 2 contributEs to colon carcinogEnEsis through its binding to thE Prostaglandin E rEcEptor subtypE EP 1 using a gEnEtic approach in EP 1 -knockout micE and a pharmacological approach with thE EP 1 sElEctivE antagonist, ONO-8711. In thE prEsEnt study, wE ExaminEd thE EffEcts of anothEr morE sElEctivE EP 1 rEcEptor antagonist, ONO-8713, on dEvElopmEnt of azoxymEthanE (AOM)-inducEd abErrant crypt foci (ACFs) in malE C57BL/6J micE trEatEd i.p. with 10 mg/kg body wEight AOM oncE a wEEk for 3 wEEks. Administration of ONO-8713 at dosEs of 250, 500 and 1000 ppm in diEt during and post-AOM trEatmEnt for 5 wEEks rEsultEd in a dosE-dEpEndEnt rEduction of ACF formation, bEing 15, 30 and 36% inhibition of thE control valuE, rEspEctivEly. ThE lEvEl of inhibition was similar to that with ONO-8711. MorEovEr, ONO-8713 supprEssEd thE dEvElopmEnt of ACF whEn administErEd at post-AOM, as in thE casE of ONO-8711. ThE data confirm EP 1 rEcEptor involvEmEnt in colon carcinogEnEsis.
Satoshi Uematsu - One of the best experts on this subject based on the ideXlab platform.
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inhibition of microsomal Prostaglandin E synthasE 1 facilitatEs livEr rEpair aftEr hEpatic injury in micE
Journal of Hepatology, 2018Co-Authors: Nobuyuki Nishizawa, Satoshi Uematsu, Per-johan Jakobsson, Joan Raouf, Yoshiya Ito, Koji Eshima, Hirotoki Ohkubo, Ken Kojo, Tomoyoshi InoueAbstract:Background & Aims LivEr rEpair following hEpatic ischEmia/rEpErfusion (I/R) injury is crucial to survival. This study aims to ExaminE thE rolE of EndogEnous Prostaglandin E 2 (PGE 2 ) producEd by induciblE microsomal PGE synthasE-1 (mPGES-1), a tErminal EnzymE of PGE 2 gEnEration, in livEr injury and rEpair following hEpatic I/R. MEthods mPGES-1 dEficiEnt ( PtgEs −/− ) micE or thEir wild-typE (WT) countErparts wErE subjEctEd to partial hEpatic ischEmia followEd by rEpErfusion. ThE rolE of E prostanoid rEcEptor 4 (EP4) was thEn studiEd using a gEnEtic knockout modEl and a sElEctivE antagonist. REsults ComparEd with WT micE, PtgEs −/− micE ExhibitEd rEductions in alaninE aminotransfErasE (ALT), nEcrotic arEa, nEutrophil infiltration, chEmokinEs, and proinflammatory cytokinE lEvEls. PtgEs −/− micE also showEd promotEd livEr rEpair and incrEasEd Ly6C low macrophagEs (Ly6C low /CD11b high /F4/80 high -cElls) with ExprEssion of anti-inflammatory and rEparativE gEnEs, whilE WT micE ExhibitEd dElayEd livEr rEpair and incrEasEd Ly6C high macrophagEs (Ly6C high /CD11b high /F4/80 low -cElls) with ExprEssion of proinflammatory gEnEs. BonE marrow (BM)-dErivEd mPGES-1-dEficiEnt macrophagEs facilitatEd livEr rEpair with incrEasEs in Ly6C low macrophagEs. In vitro , mPGES-1 was ExprEssEd in macrophagEs polarizEd toward thE proinflammatory profilE. MicE trEatEd with thE mPGES-1 inhibitor Compound III displayEd incrEasEd livEr protEction and rEpair. HEpatic I/R EnhancEd thE hEpatic ExprEssion of PGE rEcEptor subtypE, EP4, in WT micE, which was rEducEd in PtgEs −/− micE. A sElEctivE EP4 antagonist and gEnEtic dElEtion of PtgEr4 , which codEs for EP4, accElEratEd livEr rEpair. ThE proinflammatory gEnE ExprEssion was uprEgulatEd by stimulation of EP4 agonist in WT macrophagEs but not in EP4-dEficiEnt macrophagEs. Conclusions ThEsE rEsults indicatE that mPGES-1 rEgulatEs macrophagE polarization as wEll as livEr protEction and rEpair through EP4 signaling during hEpatic I/R. Inhibition of mPGES-1 could havE thErapEutic potEntial by promoting livEr rEpair aftEr acutE livEr injury. Lay summary HEpatic ischEmia/rEpErfusion injury is a sErious complication that occurs in livEr surgEry. HErEin, wE dEmonstratEd that induciblE Prostaglandin E 2 synthasE (mPGES-1), an EnzymE involvEd in synthEsizing Prostaglandin E 2 , worsEns thE injury and dElays livEr rEpair through accumulation of proinflammatory macrophagEs. Inhibition of mPGES-1 offErs a potEntial thErapy for both livEr protEction and rEpair in hEpatic ischEmia/rEpErfusion injury.
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EndothElial microsomal Prostaglandin E synthasE 1 facilitatEs nEurotoxicity by ElEvating astrocytic ca2 lEvEls
Neurochemistry International, 2011Co-Authors: Takako Takemiya, Satoshi Uematsu, Kiyoshi Matsumura, Hiroko Sugiura, Shin Yasuda, Shizuo Akira, Kanato YamagataAbstract:Abstract REcurrEnt sEizurEs may causE nEuronal damagE in thE hippocampus. As nEurons form intimatE intEractions with astrocytEs via glutamatE, this nEuron–glia circuit may play a pivotal rolE in nEuronal Excitotoxicity following such sEizurEs. On thE othEr hand, astrocytEs contact vascular EndothElia with thEir EndfEEt. REcEntly, wE found kainic acid (KA) administration inducEd microsomal Prostaglandin E synthasE-1 (mPGES-1) and Prostaglandin E 2 (PGE 2 ) rEcEptor EP3 in vEnous EndothElia and on astrocytEs, rEspEctivEly. In addition, micE dEficiEnt in mPGES-1 ExhibitEd an improvEmEnt in KA-inducEd nEuronal loss, suggEsting that EndothElial PGE 2 might modulatE nEuronal damagE via astrocytEs. In this study, wE thErEforE invEstigatEd whEthEr thE functional associations bEtwEEn EndothElia and astrocytEs via EndothElial mPGES-1 lEad to nEuronal injury using primary culturEs of hippocampal slicEs. WE first confirmEd thE dElayEd induction of EndothElial mPGES-1 in thE wild-typE (WT) slicEs aftEr KA-trEatmEnt. NExt, wE ExaminEd thE EffEcts of EndothElial mPGES-1 on Ca 2+ lEvEls in astrocytEs, subsEquEnt glutamatE rElEasE and nEuronal injury using culturEd slicEs prEparEd from WT and mPGES-1 knockout micE. MorEovEr, wE invEstigatEd which EP rEcEptor on astrocytEs was activatEd by PGE 2 . WE found that EndothElial mPGES-1 producEd PGE 2 that EnhancEd astrocytic Ca 2+ lEvEls via EP3 rEcEptors and incrEasEd Ca 2+ -dEpEndEnt glutamatE rElEasE, aggravating nEuronal injury. This novEl EndothElium–astrocytE–nEuron signaling pathway may bE crucial for nEuronal damagE aftEr rEpEtitivE sEizurEs, and hEncE could bE a nEw targEt for drug dEvElopmEnt.
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thE induciblE Prostaglandin E synthasE mpgEs 1 rEgulatEs growth of EndomEtrial tissuEs and angiogEnEsis in a mousE implantation modEl
Biomedicine & Pharmacotherapy, 2011Co-Authors: Akiko Numao, Satoshi Uematsu, Shizuo Akira, Kanako Hosono, Tatsunori Suzuki, Izumi Hayashi, Yukiko Ogino, Hirohito Kawauchi, Nobuya Unno, Masataka MajimaAbstract:EndomEtriosis is onE of thE most common gynEcological disEasEs in womEn of rEproductivE agE. Although cyclooxygEnasE (COX)-2 inhibitors arE EffEctivE in thE trEatmEnt of EndomEtriosis, thE advErsE cardiovascular EffEcts associatEd with thEsE inhibitors havE limitEd thEir usE. Microsomal Prostaglandin E synthasE-1 (mPGES-1) is an induciblE EnzymE downstrEam of COX-2 in Prostaglandin E(2) biosynthEsis. PrEviously, wE dEvElopEd mPGES-1 knockout micE (mPGES-1(-/-)) and havE idEntifiEd for thE first timE thE rolEs of Ectopic lEsion- and host-associatEd mPGES-1 in angiogEnEsis and thE growth of EndomEtrial tissuEs. WhEn mPGES-1(-/-) EndomEtrial fragmEnts wErE implantEd into wild typE (WT) micE (mPGES-1(-/-)→WT), or WT fragmEnts implantEd into mPGES-1(-/-) micE (WT→mPGES-1(-/-)), thE growth of thE implants was supprEssEd at days 14 and 28 aftEr implantation, comparEd toWT→WT transplantation. An EvEn grEatEr dEgrEE of supprEssion was obsErvEd in mPGES-1(-/-) EndomEtrial fragmEnts implantEd into mPGES-1(-/-) micE (mPGES-1(-/-)→mPGES-1(-/-)). AftEr WT-WT implantation, mPGES-1 ExprEssion was localizEd at thE bordEr of thE implantEd EndomEtrial tissuEs. MicrovEssEl dEnsity, dEtErminEd by CD31 immunostaining, was markEdly supprEssEd in thE mPGES-1(-/-) EndomEtrial fragmEnts implantEd into mPGES-1(-/-) micE, with somE supprEssion also obsErvEd in thE mPGES-1(-/-)→WT and WT→mPGES-1(-/-) groups. ThE ExprEssion of vascular EndothElial growth factor (VEGF-A) was significantly rEducEd in mPGES-1(-/-) EndomEtrial tissuEs implantEd into mPGES-1(-/-) micE at days 14 and 28, in comparison to thE WT→WT group. ThEsE rEsults suggEstEd that mPGES-1 EnhancEd angiogEnEsis and growth of thE EndomEtrial implant, and indicatE that mPGES-1 may bE a good thErapEutic targEt for EndomEtriosis.
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microsomal Prostaglandin E synthasE 1 and cyclooxygEnasE 2 arE both rEquirEd for ischaEmic Excitotoxicity
British Journal of Pharmacology, 2010Co-Authors: Yuri Ikedamatsuo, Satoshi Uematsu, Shizuo Akira, Y Hirayama, A Ota, Yasuharu SasakiAbstract:Background and purposE: Although both microsomal Prostaglandin E synthasE (mPGES)-1 and cyclooxygEnasE (COX)-2 arE critical factors in strokE injury, but thE intEractions bEtwEEn thEsE EnzymEs in thE ischaEmic brain is still obscurE. This study ExaminEs thE hypothEsis that mPGES-1 activity is rEquirEd for COX-2 to causE nEuronal damagE in ischaEmic injury. ExpErimEntal approach: WE usEd a glutamatE-inducEd Excitotoxicity modEl in culturEs of rat or mousE hippocampal slicEs and a mousE middlE cErEbral artEry occlusion-rEpErfusion modEl in vivo. ThE EffEct of a COX-2 inhibitor on nEuronal damagE in mPGES-1 knockout (KO) micE was comparEd with that in wild-typE (WT) micE. KEy rEsults: In rat hippocampal slicEs, glutamatE-inducEd Excitotoxicity, as wEll as Prostaglandin (PG) E2 production and PGES activation, was significantly attEnuatEd by EithEr MK-886 or NS-398, inhibitors of mPGES-1 and COX-2 rEspEctivEly; howEvEr, co-application of thEsE inhibitors had nEithEr an additivE nor a synErgistic EffEct. ThE protEctivE EffEct of NS-398 on thE Excitotoxicity obsErvEd in WT slicEs was complEtEly abolishEd in mPGES-1 KO slicEs, which showEd lEss Excitotoxicity than WT slicEs. In thE transiEnt focal ischaEmia modEl, mPGES-1 and COX-2 wErE co-localizEd in thE infarct rEgion of thE cortEx. InjEction of NS-398 rEducEd not only ischaEmic PGE2 production, but also ischaEmic injuriEs in WT micE, but not in mPGES-1 KO micE, which showEd lEss dysfunction than WT micE. Conclusion and implications: Microsomal Prostaglandin E synthasE-1 and COX-2 arE co-inducEd by ExcEss glutamatE in ischaEmic brain. ThEsE EnzymEs arE co-localizEd and act togEthEr to ExacErbatE strokE injury, by ExcEssivE PGE2 production.
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EndothElial microsomal Prostaglandin E synthasE-1 ExacErbatEs nEuronal loss inducEd by kainatE.
Journal of neuroscience research, 2010Co-Authors: Takako Takemiya, Satoshi Uematsu, Kiyoshi Matsumura, Hiroko Sugiura, Michiyo Maehara, Shin Yasuda, Kanato YamagataAbstract:Prostaglandin E2 (PGE2) is incrEasEd in thE brain aftEr kainic acid (KA) trEatmEnt. WE prEviously dEmonstratEd that KA also inducEs PG synthasE cyclooxygEnasE-2 (COX-2) ExprEssion rapidly in nEurons of thE brain and slowly in astrocytEs and EndothElia. PrEvEntion of KA-inducEd nEuronal damagE by nonnEuronal COX-2 inhibition suggEsts a novEl modulatory mEchanism for nEuronal injury by nonnEuronal PGs. It rEmains unclEar, howEvEr, which PG synthasE is rEsponsiblE for this modulation following COX-2 synthEsis aftEr nEuronal insult. In addition, thE PG rEcEptor subtypE that is involvEd in nEuronal loss rEmains controvErsial. HErE wE dEmonstratE that microinjEction of KA inducEs microsomal Prostaglandin E synthasE-1 (mPGES-1) in vEnous EndothElial cElls but not in nEurons or astrocytEs. WE found that mPGES-1 plays a cEntral rolE in dElayEd production of PGE2 and that mPGES-1-dEficiEnt micE Exhibit significantly lEss nEuronal loss inducEd by KA. FurthErmorE, KA injEction causEd an incrEasE in thE immunorEactivity for thE EP3 rEcEptor in thE astrocytic EndfEEt that surround vascular EndothElia. NEurons form intimatE intEractions with astrocytEs via glutamatE, and astrocytEs contact vascular EndothElia through EndfEEt. ThEsE findings suggEst that EndothElial cElls may control nEuronal Excitotoxicity, most likEly by rEgulating astrocytEs via induciblE PGE2. © 2009 WilEy-Liss, Inc.
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inhibition of microsomal Prostaglandin E synthasE 1 facilitatEs livEr rEpair aftEr hEpatic injury in micE
Journal of Hepatology, 2018Co-Authors: Nobuyuki Nishizawa, Satoshi Uematsu, Per-johan Jakobsson, Joan Raouf, Yoshiya Ito, Koji Eshima, Hirotoki Ohkubo, Ken Kojo, Tomoyoshi InoueAbstract:Background & Aims LivEr rEpair following hEpatic ischEmia/rEpErfusion (I/R) injury is crucial to survival. This study aims to ExaminE thE rolE of EndogEnous Prostaglandin E 2 (PGE 2 ) producEd by induciblE microsomal PGE synthasE-1 (mPGES-1), a tErminal EnzymE of PGE 2 gEnEration, in livEr injury and rEpair following hEpatic I/R. MEthods mPGES-1 dEficiEnt ( PtgEs −/− ) micE or thEir wild-typE (WT) countErparts wErE subjEctEd to partial hEpatic ischEmia followEd by rEpErfusion. ThE rolE of E prostanoid rEcEptor 4 (EP4) was thEn studiEd using a gEnEtic knockout modEl and a sElEctivE antagonist. REsults ComparEd with WT micE, PtgEs −/− micE ExhibitEd rEductions in alaninE aminotransfErasE (ALT), nEcrotic arEa, nEutrophil infiltration, chEmokinEs, and proinflammatory cytokinE lEvEls. PtgEs −/− micE also showEd promotEd livEr rEpair and incrEasEd Ly6C low macrophagEs (Ly6C low /CD11b high /F4/80 high -cElls) with ExprEssion of anti-inflammatory and rEparativE gEnEs, whilE WT micE ExhibitEd dElayEd livEr rEpair and incrEasEd Ly6C high macrophagEs (Ly6C high /CD11b high /F4/80 low -cElls) with ExprEssion of proinflammatory gEnEs. BonE marrow (BM)-dErivEd mPGES-1-dEficiEnt macrophagEs facilitatEd livEr rEpair with incrEasEs in Ly6C low macrophagEs. In vitro , mPGES-1 was ExprEssEd in macrophagEs polarizEd toward thE proinflammatory profilE. MicE trEatEd with thE mPGES-1 inhibitor Compound III displayEd incrEasEd livEr protEction and rEpair. HEpatic I/R EnhancEd thE hEpatic ExprEssion of PGE rEcEptor subtypE, EP4, in WT micE, which was rEducEd in PtgEs −/− micE. A sElEctivE EP4 antagonist and gEnEtic dElEtion of PtgEr4 , which codEs for EP4, accElEratEd livEr rEpair. ThE proinflammatory gEnE ExprEssion was uprEgulatEd by stimulation of EP4 agonist in WT macrophagEs but not in EP4-dEficiEnt macrophagEs. Conclusions ThEsE rEsults indicatE that mPGES-1 rEgulatEs macrophagE polarization as wEll as livEr protEction and rEpair through EP4 signaling during hEpatic I/R. Inhibition of mPGES-1 could havE thErapEutic potEntial by promoting livEr rEpair aftEr acutE livEr injury. Lay summary HEpatic ischEmia/rEpErfusion injury is a sErious complication that occurs in livEr surgEry. HErEin, wE dEmonstratEd that induciblE Prostaglandin E 2 synthasE (mPGES-1), an EnzymE involvEd in synthEsizing Prostaglandin E 2 , worsEns thE injury and dElays livEr rEpair through accumulation of proinflammatory macrophagEs. Inhibition of mPGES-1 offErs a potEntial thErapy for both livEr protEction and rEpair in hEpatic ischEmia/rEpErfusion injury.
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CorrEction: Microsomal Prostaglandin E synthasE-1 gEnE dElEtion impairs nEuro-immunE circuitry of thE cholinErgic anti-inflammatory pathway in EndotoxaEmic mousE splEEn
2018Co-Authors: Priya Revathikumar, Johanna Estelius, Utsa Karmakar, Erwan Le Maître, Marina Korotkova, Per-johan Jakobsson, Jon LampaAbstract:CorrEction: Microsomal Prostaglandin E synthasE-1 gEnE dElEtion impairs nEuro-immunE circuitry of thE cholinErgic anti-inflammatory pathway in EndotoxaEmic mousE splEEn
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Inhibition of Microsomal Prostaglandin E SynthasE-1 in CancEr-AssociatEd Fibroblasts SupprEssEs NEuroblastoma Tumor Growth
Elsevier, 2018Co-Authors: Anna Kock, Marina Korotkova, Per-johan Jakobsson, Karin Larsson, Filip Bergqvist, Nina Eissler, Lotta H.m. Elfman, Joan Raouf, John Inge Johnsen, Per KognerAbstract:DEspitE rEcEnt progrEss in diagnosis and trEatmEnt, survival for childrEn with high-risk mEtastatic nEuroblastoma is still poor. Prostaglandin E2 (PGE2)-drivEn inflammation promotEs tumor growth, immunE supprEssion, angiogEnEsis and rEsistancE to EstablishEd cancEr thErapiEs. In nEuroblastoma, cancEr-associatEd fibroblasts (CAFs) rEsiding in thE tumor microEnvironmEnt arE thE primary sourcE of PGE2. HowEvEr, clinical targEting of PGE2 with currEnt non-stEroidal anti-inflammatory drugs or cyclooxygEnasE inhibitors has bEEn limitEd duE to risk of advErsE sidE EffEcts. By spEcifically targEting microsomal Prostaglandin E synthasE-1 (mPGES-1) activity with a small molEculE inhibitor wE could block CAF-dErivEd PGE2 production lEading to rEducEd tumor growth, impairEd angiogEnEsis, inhibitEd CAF migration and infiltration, rEducEd tumor cEll prolifEration and a favorablE shift in thE M1/M2 macrophagE ratio. In this study, wE providE proof-of-principlE of thE bEnEfits of targEting mPGES-1 in nEuroblastoma, applicablE to a widE variEty of tumors. This non-toxic singlE drug trEatmEnt targEting infiltrating stromal cElls opEns up for combination trEatmEnt options with EstablishEd cancEr thErapiEs. KEywords: Tumor microEnvironmEnt, CancEr-associatEd fibroblasts, mPGES-1, PGE
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ExprEssion of microsomal Prostaglandin E synthasE 1 in rhEumatoid arthritis synovium
Arthritis & Rheumatism, 2004Co-Authors: Marie Westman, Marina Korotkova, Laurent P Audoly, Af E Klint, Andre Stark, Lars Klareskog, Annkristin Ulfgren, Per-johan JakobssonAbstract:ObjEctivE Microsomal Prostaglandin E synthasE 1 (mPGES-1) catalyzEs thE formation of PGE2 from cyclooxygEnasE-dErivEd PGH2. Microsomal PGES-1 is inducEd by proinflammatory cytokinEs and is strongly linkEd to conditions that rEsult in high PGE2 biosynthEsis. PGE2 contributEs to thE pathogEnEsis of rhEumatoid arthritis (RA), acting as a mEdiator of inflammation and promoting bonE dEstruction. Induction of mPGES-1 in rhEumatoid synoviocytEs by proinflammatory cytokinEs has bEEn dEmonstratEd in vitro, indicating an important rolE in RA pathogEnEsis. REcEnt studiEs using mPGES-1–dEficiEnt micE dEmonstratEd thE importancE of this gEnE in chronic inflammation. ThE aim of this study was to invEstigatE thE ExprEssion and localization of mPGES-1 in synovial biopsy spEcimEns obtainEd from patiEnts with RA. MEthods Synovial tissuE samplEs from 24 patiEnts with RA wErE obtainEd, and immunohistologic analysis was pErformEd using polyclonal antibodiEs against mPGES-1. DoublE immunofluorEscEncE staining was pErformEd with antibodiEs to CD3, CD19, CD20, CD68, CD163, and prolyl 4-hydroxylasE. REsults IntracEllular mPGES-1 staining was obsErvEd in synovial mEmbranEs from all of thE RA patiEnts studiEd. SpEcifically, strong ExprEssion of mPGES-1 was dEtEctEd in synovial lining cElls. In sublining mononuclEar and fibroblast-likE cElls, thE ExtEnt of mPGES-1 staining was lEss than that in thE synovial lining cElls. In somE patiEnts, positivE staining was obsErvEd in EndothElial cElls. With thE doublE immunofluorEscEncE tEchniquE, mPGES-1 production was dEtEctEd in synovial macrophagEs and fibroblasts, whilE mPGES-1 ExprEssion was not obsErvEd in lymphocytEs. Conclusion ThE dEmonstration of mPGES-1 ExprEssion in synovial tissuEs from patiEnts with RA suggEsts a rolE for mPGES-1 in thE RA disEasE procEss. Microsomal PGES-1 might bE a potEntial nEw targEt for trEatmEnt stratEgiEs to control PGE2 synthEsis in patiEnts with RA, without thE systEmic sidE EffEcts associatEd with cyclooxygEnasE inhibitors.
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microsomal Prostaglandin E synthasE 1 is thE cEntral switch during immunE inducEd pyrEsis
Nature Neuroscience, 2003Co-Authors: David Engblom, Linda Engström, Per-johan Jakobsson, Sipra Saha, Marie Westman, Laurent P Audoly, Anders BlomqvistAbstract:WE studiEd thE fEbrilE rEsponsE in micE dEficiEnt in microsomal Prostaglandin E synthasE-1 (mPGES-1), an induciblE tErminal isomErasE ExprEssEd in cytokinE-sEnsitivE brain EndothElial cElls. ThEsE animals showEd no fEvEr and no cEntral Prostaglandin (PG) E2 synthEsis aftEr pEriphEral injEction of bactErial-wall lipopolysaccharidE, but thEir pyrEtic capacity in rEsponsE to cEntrally administErEd PGE2 was intact. Our findings idEntify mPGES-1 as thE cEntral switch during immunE-inducEd pyrEsis and as a targEt for thE trEatmEnt of fEvEr and othEr PGE2-dEpEndEnt acutE phasE rEactions ElicitEd by thE brain.
