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1.
Nat Immunol ; 15(11): 1064-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25240383

RESUMO

It remains largely unclear how antigen-presenting cells (APCs) encounter effector or memory T cells efficiently in the periphery. Here we used a mouse contact hypersensitivity (CHS) model to show that upon epicutaneous antigen challenge, dendritic cells (DCs) formed clusters with effector T cells in dermal perivascular areas to promote in situ proliferation and activation of skin T cells in a manner dependent on antigen and the integrin LFA-1. We found that DCs accumulated in perivascular areas and that DC clustering was abrogated by depletion of macrophages. Treatment with interleukin 1α (IL-1α) induced production of the chemokine CXCL2 by dermal macrophages, and DC clustering was suppressed by blockade of either the receptor for IL-1 (IL-1R) or the receptor for CXCL2 (CXCR2). Our findings suggest that the dermal leukocyte cluster is an essential structure for elicitating acquired cutaneous immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Dermatite de Contato/imunologia , Pele/imunologia , Animais , Antígeno CD11c/genética , Proliferação de Células , Quimiocina CXCL2/biossíntese , Feminino , Memória Imunológica/imunologia , Interleucina-1alfa/farmacologia , Ativação Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Neutrófilos/imunologia , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Pele/patologia
2.
Nat Immunol ; 14(6): 554-63, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23624557

RESUMO

Microenvironment-based alterations in phenotypes of mast cells influence the susceptibility to anaphylaxis, yet the mechanisms underlying proper maturation of mast cells toward an anaphylaxis-sensitive phenotype are incompletely understood. Here we report that PLA2G3, a mammalian homolog of anaphylactic bee venom phospholipase A2, regulates this process. PLA2G3 secreted from mast cells is coupled with fibroblastic lipocalin-type PGD2 synthase (L-PGDS) to provide PGD2, which facilitates mast-cell maturation via PGD2 receptor DP1. Mice lacking PLA2G3, L-PGDS or DP1, mast cell-deficient mice reconstituted with PLA2G3-null or DP1-null mast cells, or mast cells cultured with L-PGDS-ablated fibroblasts exhibited impaired maturation and anaphylaxis of mast cells. Thus, we describe a lipid-driven PLA2G3-L-PGDS-DP1 loop that drives mast cell maturation.


Assuntos
Fosfolipases A2 do Grupo III/imunologia , Mastócitos/imunologia , Comunicação Parácrina/imunologia , Prostaglandina D2/imunologia , Receptores de Prostaglandina/imunologia , Animais , Western Blotting , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/imunologia , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Fosfolipases A2 do Grupo III/genética , Fosfolipases A2 do Grupo III/metabolismo , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/genética , Lipocalinas/imunologia , Lipocalinas/metabolismo , Mastócitos/metabolismo , Mastócitos/ultraestrutura , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Análise de Sequência com Séries de Oligonucleotídeos , Comunicação Parácrina/genética , Prostaglandina D2/metabolismo , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
3.
Int J Mol Sci ; 25(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38339119

RESUMO

Prostaglandins are bioactive compounds, and the activation of their receptors affects the expression of clock genes. However, the prostaglandin F receptor (Ptgfr) has no known relationship with biological rhythms. Here, we first measured the locomotor period lengths of Ptgfr-KO (B6.129-Ptgfrtm1Sna) mice and found that they were longer under constant dark conditions (DD) than those of wild-type (C57BL/6J) mice. We then investigated the clock gene patterns within the suprachiasmatic nucleus in Ptgfr-KO mice under DD and observed a decrease in the expression of the clock gene cryptochrome 1 (Cry1), which is related to the circadian cycle. Moreover, the expression of Cry1, Cry2, and Period2 (Per2) mRNA were significantly altered in the mouse liver in Ptgfr-KO mice under DD. In the wild-type mouse, the plasma prostaglandin F2α (PGF2α) levels showed a circadian rhythm under a 12 h cycle of light-dark conditions. In addition, in vitro experiments showed that the addition of PTGFR agonists altered the amplitude of Per2::luc activity, and this alteration differed with the timing of the agonist addition. These results lead us to hypothesize that the plasma rhythm of PGF2α is important for driving clock genes, thus suggesting the involvement of PGF2α- and Ptgfr-targeting drugs in the biological clock cycle.


Assuntos
Ritmo Circadiano , Dinoprosta , Camundongos , Animais , Dinoprosta/metabolismo , Camundongos Endogâmicos C57BL , Ritmo Circadiano/genética , Relógios Biológicos , Núcleo Supraquiasmático/metabolismo , Expressão Gênica , Criptocromos/genética , Criptocromos/metabolismo
4.
Pharmacol Rev ; 72(4): 910-968, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32962984

RESUMO

Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT: In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.


Assuntos
Receptores de Prostaglandina E/metabolismo , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Dinoprostona/imunologia , Dinoprostona/metabolismo , Epoprostenol/imunologia , Epoprostenol/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Polimorfismo de Nucleotídeo Único , Multimerização Proteica , Ratos , Receptores de Prostaglandina E/química , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/imunologia , Especificidade da Espécie
5.
Biochem Biophys Res Commun ; 589: 139-146, 2022 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-34920379

RESUMO

The ω3 polyunsaturated fatty acids (PUFAs) are known to have beneficial effects on health and diseases, and hence their intake is encouraged. However, it remains unknown as to how ω3 PUFAs affect female reproduction processes, in which ω6 PUFA-derived prostaglandin (PG) E2 and PGF2α play crucial roles. We therefore compared female reproductive performance between ω3 PUFA-biased linseed oil diet-fed (Lin) mice and ω6 PUFA-biased soybean oil diet-fed (Soy) mice. In Lin mice, the uterine levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) were 0.42 fold and 16 fold of those in Soy mice, respectively, with the EPA/AA ratio being 0.7 (vs 0.02 in Soy mice). Lin mice showed no alterations in any of the fertility indexes, including luteolysis and parturition. The uterine PG synthesis profiles of Lin mice were similar to those of Soy mice, but the levels of PGF2α and PGE2 were 50% of those in Soy mice, as a result of the increased EPA/AA ratio. PGF3α and PGE3 were undetectable in the uterine tissues of Soy and Lin mice. Interestingly, in Lin mice, 'luteolytic' PGF2α synthesis was considerably maintained even in the ω6 PUFA-reduced condition. These results suggest the existence of an elaborate mechanism securing PGF2α synthesis to a level that is sufficient for triggering luteolysis and parturition, even under ω6 PUFA-reduced conditions.


Assuntos
Dieta , Ácidos Graxos Ômega-3/farmacologia , Luteólise/fisiologia , Parto/fisiologia , Prostaglandinas/biossíntese , Útero/metabolismo , Animais , Feminino , Luteólise/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Parto/efeitos dos fármacos , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Reprodução/efeitos dos fármacos , Útero/efeitos dos fármacos
6.
Biol Pharm Bull ; 45(8): 992-997, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35908909

RESUMO

Prostanoids are a group of typical lipid mediators that are biosynthesized from arachidonic acid by the actions of cyclooxygenases and their subsequent terminal synthases. Prostanoids exert a wide variety of actions through their specific membrane receptors on target cells. In addition to their classical actions, including fever, pain, and inflammation, prostanoids have been shown to play pivotal roles in various biological processes, such as female reproduction and the maintenance of vascular and gut homeostasis. Moreover, recent research using mice deficient in each of the prostanoid receptors, or using agonists/antagonists specific for each receptor clarified novel actions of prostanoids that had long been unknown, and the mechanisms therein. In this review, we introduce recent advances in the fields of metabolic control by prostanoid receptors such as in adipocyte differentiation, lipolysis, and adipocyte browning in adipose tissues, and discuss the potential of prostanoid receptors as a treatment target for metabolic disorders.


Assuntos
Prostaglandinas , Receptores de Prostaglandina , Adipócitos/metabolismo , Animais , Feminino , Inflamação/metabolismo , Lipólise , Camundongos , Prostaglandinas/fisiologia , Receptores de Prostaglandina/metabolismo
7.
EMBO J ; 36(14): 2146-2160, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28588064

RESUMO

During pregnancy, up-regulation of heparin-binding (HB-) EGF and cyclooxygenase-2 (COX-2) in the uterine epithelium contributes to decidualization, a series of uterine morphological changes required for placental formation and fetal development. Here, we report a key role for the lipid mediator lysophosphatidic acid (LPA) in decidualization, acting through its G-protein-coupled receptor LPA3 in the uterine epithelium. Knockout of Lpar3 or inhibition of the LPA-producing enzyme autotaxin (ATX) in pregnant mice leads to HB-EGF and COX-2 down-regulation near embryos and attenuates decidual reactions. Conversely, selective pharmacological activation of LPA3 induces decidualization via up-regulation of HB-EGF and COX-2. ATX and its substrate lysophosphatidylcholine can be detected in the uterine epithelium and in pre-implantation-stage embryos, respectively. Our results indicate that ATX-LPA-LPA3 signaling at the embryo-epithelial boundary induces decidualization via the canonical HB-EGF and COX-2 pathways.


Assuntos
Decídua/crescimento & desenvolvimento , Embrião de Mamíferos/fisiologia , Lisofosfolipídeos/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais , Útero/fisiologia , Animais , Ciclo-Oxigenase 2/metabolismo , Desenvolvimento Embrionário , Feminino , Técnicas de Inativação de Genes , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Camundongos , Camundongos Knockout , Receptores de Ácidos Lisofosfatídicos/deficiência
8.
Genes Cells ; 25(3): 197-214, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31989743

RESUMO

Cell competition is a biological process by which unfit cells are eliminated from "cell society." We previously showed that cultured mammalian epithelial Madin-Darby canine kidney (MDCK) cells expressing constitutively active YAP were eliminated by apical extrusion when surrounded by "normal" MDCK cells. However, the molecular mechanism underlying the elimination of active YAP-expressing cells was unknown. Here, we used high-throughput chemical compound screening to identify cyclooxygenase-2 (COX-2) as a key molecule triggering cell competition. Our work shows that COX-2-mediated PGE2 secretion engages its receptor EP2 on abnormal and nearby normal cells. This engagement of EP2 triggers downstream signaling via an adenylyl cyclase-cyclic AMP-PKA pathway that, in the presence of active YAP, induces E-cadherin internalization leading to apical extrusion. Thus, COX-2-induced PGE2 appears a warning signal to both abnormal and surrounding normal cells to drive cell competition.


Assuntos
Competição entre as Células , Proteínas de Ciclo Celular/metabolismo , Dinoprostona/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Animais , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Cães , Ensaios de Triagem em Larga Escala , Humanos , Células Madin Darby de Rim Canino/metabolismo
9.
Int Arch Allergy Immunol ; 182(9): 788-799, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33873179

RESUMO

INTRODUCTION: Epicutaneous (e.c.) allergen exposure is an important route of sensitization toward allergic diseases in the atopic march. Allergen sources such as house dust mites contain proteases that involve in the pathogenesis of allergy. Prostanoids produced via pathways downstream of cyclooxygenases (COXs) regulate immune responses. Here, we demonstrate effects of COX inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) on e.c. sensitization to protease allergen and subsequent airway inflammation in mice. METHODS: Mice were treated with NSAIDs during e.c. sensitization to a model protease allergen, papain, and/or subsequent intranasal challenge with low-dose papain. Serum antibodies, cytokine production in antigen-restimulated skin or bronchial draining lymph node (DLN) cells, and airway inflammation were analyzed. RESULTS: In e.c. sensitization, treatment with a nonspecific COX inhibitor, indomethacin, promoted serum total and papain-specific IgE response and Th2 and Th17 cytokine production in skin DLN cells. After intranasal challenge, treatment with indomethacin promoted allergic airway inflammation and Th2 and Th17 cytokine production in bronchial DLN cells, which depended modestly or largely on COX inhibition during e.c. sensitization or intranasal challenge, respectively. Co-treatment with COX-1-selective and COX-2-selective inhibitors promoted the skin and bronchial DLN cell Th cytokine responses and airway inflammation more efficiently than treatment with either selective inhibitor. CONCLUSION: The results suggest that the overall effects of COX downstream prostanoids are suppressive for development and expansion of not only Th2 but also, unexpectedly, Th17 upon exposure to protease allergens via skin or airways and allergic airway inflammation.


Assuntos
Alérgenos/imunologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Peptídeo Hidrolases/imunologia , Células Th17/imunologia , Células Th2/imunologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Diferenciação Celular , Feminino , Imunização , Camundongos , Papaína/imunologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
10.
Nat Chem Biol ; 15(1): 18-26, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30510193

RESUMO

Prostaglandin E receptor EP4, a G-protein-coupled receptor, is involved in disorders such as cancer and autoimmune disease. Here, we report the crystal structure of human EP4 in complex with its antagonist ONO-AE3-208 and an inhibitory antibody at 3.2 Å resolution. The structure reveals that the extracellular surface is occluded by the extracellular loops and that the antagonist lies at the interface with the lipid bilayer, proximal to the highly conserved Arg316 residue in the seventh transmembrane domain. Functional and docking studies demonstrate that the natural agonist PGE2 binds in a similar manner. This structural information also provides insight into the ligand entry pathway from the membrane bilayer to the EP4 binding pocket. Furthermore, the structure reveals that the antibody allosterically affects the ligand binding of EP4. These results should facilitate the design of new therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.


Assuntos
Receptores de Prostaglandina E Subtipo EP4/química , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Regulação Alostérica , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Sítios de Ligação , Caprilatos/química , Caprilatos/metabolismo , Cristalografia por Raios X , Epoprostenol/análogos & derivados , Epoprostenol/química , Epoprostenol/metabolismo , Humanos , Ligantes , Bicamadas Lipídicas , Simulação de Acoplamento Molecular , Naftalenos/química , Naftalenos/metabolismo , Éteres Fenílicos/química , Éteres Fenílicos/metabolismo , Fenilbutiratos/química , Fenilbutiratos/metabolismo , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/genética , Spodoptera/genética
11.
J Nat Prod ; 84(10): 2738-2743, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34612636

RESUMO

A simple methylenedioxy dibromoindole alkaloid, amakusamine (1), was isolated from a marine sponge of the genus Psammocinia, and its structure was determined from spectroscopic data, time-dependent density-functional theory calculations, and synthesis. Compound 1 inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts with an IC50 value of 10.5 µM in RAW264 cells. The structure-activity relationship of 1 was also investigated with synthetic derivatives.


Assuntos
Alcaloides/farmacologia , Osteoclastos/efeitos dos fármacos , Poríferos/química , Ligante RANK/antagonistas & inibidores , Animais , Japão , Camundongos , Estrutura Molecular , Células RAW 264.7 , Relação Estrutura-Atividade
12.
J Nat Prod ; 84(9): 2475-2485, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34464116

RESUMO

Fifteen new isopimarane-type diterpenes, taichunins E-S (1-15), and a new 20-nor-isopimarane, taichunin T (16), together with four known compounds were isolated from Aspergillus taichungensis (IBT 19404). The structures of these new compounds were determined by NMR and mass spectroscopy, and their absolute configurations were analyzed by NOESY and TDDFT calculations of ECD spectra. Taichunins G, K, and N (3, 7, and 10) completely inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts in RAW264 cells at 5 µM, with 3 showing 92% inhibition at a concentration of 0.2 µM.


Assuntos
Abietanos/farmacologia , Aspergillus/química , Osteoclastos/efeitos dos fármacos , Ligante RANK , Abietanos/isolamento & purificação , Animais , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Camundongos , Estrutura Molecular , Células RAW 264.7 , Taiwan
13.
Int Immunol ; 31(9): 597-606, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30926983

RESUMO

Prostaglandins (PGs) are the major lipid mediators in animals and which are biosynthesized from arachidonic acid by the cyclooxygenases (COX-1 or COX-2) as the rate-limiting enzymes. Prostaglandin E2 (PGE2), which is the most abundantly detected PG in various tissues, exerts versatile physiological and pathological actions via four receptor subtypes (EP1-4). Non-steroidal anti-inflammatory drugs, such as aspirin and indomethacin, exert potent anti-inflammatory actions by the inhibition of COX activity and the resulting suppression of PG production. Therefore, PGE2 has been shown to exacerbate several inflammatory responses and immune diseases. Recently, studies using mice deficient in each PG receptor subtype have clarified the detailed mechanisms underlying PGE2-associated inflammation and autoimmune diseases involving each EP receptor. Here, we review the recent advances in our understanding of the roles of PGE2 receptors in the progression of acute and chronic inflammation and autoimmune diseases. PGE2 induces acute inflammation through mast cell activation via the EP3 receptor. PGE2 also induces chronic inflammation and various autoimmune diseases through T helper 1 (Th1)-cell differentiation, Th17-cell proliferation and IL-22 production from Th22 cells via the EP2 and EP4 receptors. The possibility of EP receptor-targeted drug development for the treatment of immune diseases is also discussed.


Assuntos
Dinoprostona/imunologia , Doenças do Sistema Imunitário/imunologia , Inflamação/imunologia , Animais , Humanos , Prostaglandina-Endoperóxido Sintases/imunologia
14.
Biol Pharm Bull ; 43(4): 649-662, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238706

RESUMO

Multiple external and internal factors have been reported to induce thymic involution. Involution involves dramatic reduction in size and function of the thymus, leading to various immunodeficiency-related disorders. Therefore, clarifying and manipulating molecular mechanisms governing thymic involution are clinically important, although only a few studies have dealt with this issue. In the present study, we investigated the molecular mechanisms underlying thymic involution using a murine acute diet-restriction model. Gene expression analyses indicated that the expression of T helper 1 (Th1)-producing cytokines, namely interferon-γ and interleukin (IL)-2, was down-regulated, while that of Th2-producing IL-5, IL-6, IL-10 and IL-13 was up-regulated, suggesting that acute diet-restriction regulates the polarization of naïve T cells to a Th2-like phenotype during thymic involution. mRNAs for prostanoid biosynthetic enzymes were up-regulated by acute diet-restriction. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses detected the increased production of prostanoids, particularly prostaglandin D2 and thromboxane B2, a metabolite of thromboxane A2, in the diet-restricted thymus. Administration of non-steroidal anti-inflammatory drugs, namely aspirin and etodolac, to inhibit prostanoid synthesis suppressed the biased expression of Th1- and Th2-cytokines as well as molecular markers of Th1 and Th2 cells in the diet-restricted thymus, without affecting the reduction of thymus size. In vitro stimulation of thymocytes with phorbol myristate acetate (PMA)/ionomycin confirmed the polarization of thymocytes from diet-restricted mice toward Th2 cells. These results indicated that the induced production of prostanoids during diet-restriction-induced thymic involution is involved in the polarization of naïve T cells in the thymus.


Assuntos
Restrição Calórica , Citocinas/imunologia , Prostaglandinas/imunologia , Células Th1/imunologia , Células Th2/imunologia , Timo/imunologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Aspirina/farmacologia , Citocinas/genética , Dieta , Etodolac/farmacologia , Masculino , Camundongos Endogâmicos ICR , Tamanho do Órgão/efeitos dos fármacos , Timo/anatomia & histologia , Timo/efeitos dos fármacos
15.
J Allergy Clin Immunol ; 144(4): 1036-1049, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31378305

RESUMO

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by IL-17-mediated immune responses. p38 is known to be highly activated in the psoriatic epidermis; however, whether p38 is involved in the development of psoriasis is unclear. OBJECTIVE: We sought to demonstrate that activation of p38 mitogen-activated protein kinase is sufficient to induce psoriatic inflammation in mice and that cutaneous p38 activities are the topical therapeutic targets for psoriasis. METHODS: A p38 activator, anisomycin, was applied daily to murine skin. Transcriptomic analyses were performed to evaluate the similarities of the skin responses to those in human psoriasis and the existing animal model. BIRB796, a small-molecule inhibitor targeting p38 activities, was applied to the murine psoriatic models topically or to human psoriatic skin specimens ex vivo. RESULTS: Topical treatment with anisomycin induced key signatures in psoriasis, such as epidermal thickening, neutrophil infiltration, and gene expression of Il1a, Il1b, Il6, Il24, Cxcl1, Il23a, and Il17a, in treated murine skin. These responses were fully abrogated by topical treatment with BIRB796, and were reduced in IL-17A-deficient mice. Transcriptomic analyses demonstrated the similarities of anisomycin-induced dermatitis to human psoriasis and imiquimod-induced murine psoriatic dermatitis. Furthermore, BIRB796 targeting of p38 activities reduced expression of psoriasis-related genes in both human keratinocytes stimulated with recombinant IL-17A in vitro and psoriatic skin specimens ex vivo. CONCLUSION: Therefore our findings suggest that cutaneous p38 activation can be a key event in patients with psoriasis and a potential topical therapeutic target of a small molecule.


Assuntos
Dermatite/metabolismo , Psoríase/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adulto , Idoso , Animais , Anisomicina/farmacologia , Dermatite/imunologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Ativadores de Enzimas/farmacologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Psoríase/imunologia , Pele/metabolismo , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
16.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1862(6): 615-622, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28336329

RESUMO

We previously demonstrated that the aromatic moiety of Tyr143 within the intracellular loop 2 (ICL2) region of the prostaglandin EP2 receptor plays a crucial role in Gs coupling. Here we investigated whether the ICL2 of the EP2 receptor directly binds to Gαs and whether an aromatic moiety affects this interaction. In Chinese hamster ovary cells, mutations of Tyr143 reduced the ability of the EP2 receptor to interact with G proteins as demonstrated by GTPγS sensitivity, as well as the ability of agonist-induced cAMP formation, with the rank order of Phe>Tyr (wild-type)=Trp>Leu>Ala (=0). We found that the wild-type ICL2 peptide (i2Y) and its mutant with Phe at Tyr143 (i2F) inhibited receptor-G protein complex formation of wild-type EP2 in membranes, whereas the Ala-substituted mutant (i2A) did not. Specific interactions between these peptides and the Gαs protein were detected by surface plasmon resonance, but Gαs showed different association rates, with a rank order of i2F>i2Y≫i2A, with similar dissociation rates. Moreover, i2F and i2Y, but not i2A activated membrane adenylyl cyclase. These results indicate that the ICL2 region of the EP2 receptor is its potential interaction site with Gαs, and that the aromatic side chain moiety at position 143 is a determinant for the accessibility of the ICL2 to the Gαs protein.


Assuntos
Cromograninas/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Substituição de Aminoácidos , Animais , Cromograninas/química , Cromograninas/genética , Cricetinae , Subunidades alfa Gs de Proteínas de Ligação ao GTP/química , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Mutação de Sentido Incorreto , Domínios Proteicos , Estrutura Secundária de Proteína , Receptores de Prostaglandina E Subtipo EP2/química , Receptores de Prostaglandina E Subtipo EP2/genética
17.
Bioorg Med Chem Lett ; 27(22): 4975-4978, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29037945

RESUMO

The marine-derived Aspergillus protuberus MF297-2 and the terrestrial A. amoenus NRRL 35600 produce enantiomeric prenylated indole alkaloids. Investigation of biological activities of the natural and synthetic derivatives revealed that (-)-enantiomers of notoamides A and B, 6-epi-notoamide T, and stephacidin A inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclastogenic differentiation of murine RAW264 cells more strongly than their respective (+)-enantiomers. Among them, (-)-6-epi-notoamide T was the most potent inhibitor with an IC50 value of 1.7µM.


Assuntos
Alcaloides Indólicos/química , Ligante RANK/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Fungos/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Concentração Inibidora 50 , Camundongos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Células RAW 264.7 , Estereoisomerismo
18.
J Biol Chem ; 290(50): 29781-93, 2015 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-26475855

RESUMO

The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1(-/-)) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4(-/-) mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors.


Assuntos
Divisão Celular , Dinoprostona/metabolismo , Melanoma Experimental/patologia , Metástase Neoplásica , Neovascularização Patológica , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Transdução de Sinais , Células Estromais/patologia , Animais , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/metabolismo , Camundongos , Camundongos Knockout
19.
Biochim Biophys Acta ; 1851(4): 414-21, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25038274

RESUMO

Prostaglandin E2 (PGE2) is one of the most typical lipid mediators produced from arachidonic acid (AA) by cyclooxygenase (COX) as the rate-limiting enzyme, and acts on four kinds of receptor subtypes (EP1-EP4) to elicit its diverse actions including pyrexia, pain sensation, and inflammation. Recently, the molecular mechanisms underlying the PGE2 actions mediated by each EP subtype have been elucidated by studies using mice deficient in each EP subtype as well as several compounds highly selective to each EP subtype, and their findings now enable us to discuss how PGE2 initiates and exacerbates inflammation at the molecular level. Here, we review the recent advances in PGE2 receptor research by focusing on the activation of mast cells via the EP3 receptor and the control of helper T cells via the EP2/4 receptor, which are the molecular mechanisms involved in PGE2-induced inflammation that had been unknown for many years. We also discuss the roles of PGE2 in acute inflammation and inflammatory disorders, and the usefulness of anti-inflammatory therapies that target EP receptors. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".


Assuntos
Dinoprostona/metabolismo , Inflamação/metabolismo , Receptores de Prostaglandina E/metabolismo , Transdução de Sinais , Animais , Anti-Inflamatórios/farmacologia , Dinoprostona/química , Dinoprostona/imunologia , Desenho de Fármacos , Humanos , Inflamação/imunologia , Inflamação/prevenção & controle , Ativação Linfocitária , Mastócitos/imunologia , Mastócitos/metabolismo , Estrutura Molecular , Terapia de Alvo Molecular , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/imunologia , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP3/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-Atividade , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
20.
Biochem Biophys Res Commun ; 470(4): 804-10, 2016 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-26820529

RESUMO

Prostaglandins (PGs) play important roles in diverse physiological processes in the central nervous system. PGD2 is the most abundant PG in the brain and acts through specific receptors, DP1 and CRTH2. We investigated the effects of PGD2 on the morphology of the hypothalamic cell line mHypoE-N37 (N37). In N37 cells, serum starvation induced neurite outgrowth and PGD2 elicited neurite retraction, although we failed to detect transcripts for DP1 and CRTH2. Such an effect of PGD2 was efficiently mimicked by its metabolite, 15-deoxy-Δ(12,14)-prostaglandin J2. N-acetyl cysteine completely abolished the effect of PGD2, and reactive oxygen species (ROS) were considered to be important. Notably, neurite outgrowth was restored by PGD2 removal. These results suggest that PGD2 induces reversible neurite retraction in a ROS-mediated mechanism that does not involve any known receptor.


Assuntos
Crescimento Celular/efeitos dos fármacos , Hipotálamo/citologia , Hipotálamo/metabolismo , Neuritos/fisiologia , Prostaglandina D2/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Hipotálamo/efeitos dos fármacos , Camundongos , Neuritos/efeitos dos fármacos , Neuritos/ultraestrutura
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