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BACKGROUND: Allergic asthma affects nearly 300 million people worldwide and causes ahigh burden of disability and death. Effective treatments rely heavily on corticosteroids, which are associated with various complications. So, the alternative treatment is of significance. Hispidulin is a bioflavonoid found in herbs that were used in traditional medicine to treat inflammatory diseases, including asthma. This study aims to investigate the efficacy of hispidulin compound in the treatment of allergic lung inflammation using the mouse model of allergic asthma. METHODS: BALB/c mice were sensitized and challenged with chicken egg ovalbumin. Cells and cytokines from bronchoalveolar lavage (BAL) fluid were examined. Lung tissues were collected for histologic study. Mouse splenic CD4+ cells were cultured to observe the effect of hispidulin on T-helper 2 (Th2) cell differentiation in vitro. RESULTS: Hispidulin treatment could alleviate allergic airway inflammation as evidenced by a significant reduction in the inflammatory cell count and Th2 cytokines interleukin (IL)-4, IL-5, IL-13 in BAL fluid. Histologic examination of lung tissues revealed lower inflammatory cell infiltration to the bronchi and less airway goblet cell hyperplasia in the treatment group compared to the control group. At the cellular level, hispidulin (25, 50, and 100 µM) was found to directly suppress the differentiation and proliferation of Th2 cells and to suppress the production of Th2 cytokines, such as IL-4, IL-5, and IL-13, in vitro. CONCLUSIONS: Hispidulin treatment was shown to effectively decrease type 2 lung inflammation in an ovalbumin-induced allergic asthma mouse model by directly suppressing Th2 cell differentiation and functions.
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Asma , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Ovalbúmina , Células Th2 , Animales , Asma/tratamiento farmacológico , Asma/inmunología , Ovalbúmina/inmunología , Células Th2/inmunología , Ratones , Femenino , Neumonía/inmunología , Neumonía/tratamiento farmacológico , Citocinas/metabolismo , Flavonas/farmacología , Flavonas/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Pulmón/patología , Pulmón/inmunología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunologíaRESUMEN
BACKGROUND: Transforming growth factor-ß (Tgf-ß) plays an important role in the pathogenesis of asthma through the regulation of T cells and airway epithelium. Its functions in alveolar macrophage (AM) during allergic airway inflammation remain unknown. METHODS: A murine asthma model was induced with ovalbumin (ova) in TßRICA/Fsp1-Cre transgenic mice expressing constitutively active Tgf-ß receptor type I (TßRICA) under the control of Fsp1-Cre transgene. Cells in the bronchoalveolar lavage (BAL) were collected to study immune cell infiltration in the lungs. Cytokine levels in BAL fluid were measured by enzyme-linked immunoassay (ELISA). Lungs were sectioned and stained with hematoxylin and eosin, periodic acid-Schiff, and trichrome for histopathologic evaluation. AMs were assessed by flow cytometry and were sorted for quantitative polymerase chain reaction analysis. RESULTS: Our data indicated that TßRICA transcripts were induced in AMs of TßRICA/Fsp1-Cre mice. Following the ova challenges, TßRICA/Fsp1-Cre mice exhibited reduced cellular infiltration of the airway, reduced pulmonary fibrosis, and reduced bronchial mucus secretion as compared to ova-challenged wild-type mice. An alternatively activated macrophage (M2) polarization was significantly elevated in the lungs of ova-challenged TßRICA/Fsp1-Cre mice as reflected by increased numbers of AMs expressing M2 subtype marker, CD163, in the lungs and enhanced expression of CCR2 and CD206 in AMs. Moreover, TßRICA/Fsp1-Cre AMs showed augmented expression of transcription factors, Foxo1, and IRF4, which are known to be positive regulators for M2 polarization. CONCLUSIONS: Expression of TßRICA in AMs promoted M2 polarization and ameliorated allergic airway inflammation in an ova-induced asthma mouse model.
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Asma , Macrófagos Alveolares , Ratones , Humanos , Animales , Ovalbúmina/efectos adversos , Asma/metabolismo , Pulmón/patología , Inflamación , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Ratones Endogámicos BALB CRESUMEN
Allergic contact dermatitis (ACD) is a type IV hypersensitivity mainly mediated by Th1/Th17 immune response. Topical corticosteroid is currently the first-line treatment for allergic contact dermatitis (ACD) and systemic administration of immunosuppressive drugs are used in patients with severe disseminated cases. However, increased risk of adverse effects has limited their use. Thus, the development of a novel immunosuppressant for ACD with low toxicity is a challenging issue. In this study, we began our study by using a murine contact hypersensitivity (CHS) model of ACD to examine the immunosuppressive effects of DYRK1B inhibition. We found that mice treated with a selective DYRK1B inhibitor show reduced ear inflammation. In addition, a significant reduction of Th1 and Th17 cells in the regional lymph node upon DYRK1B inhibition was observed by FACS analysis. Studies in vitro further revealed that DYRK1B inhibitor does not only suppressed Th1 and Th17 differentiation, but also promotes regulatory T cells (Treg) differentiation. Mechanistically, FOXO1 signaling was enhanced due to the suppression of FOXO1Ser329 phosphorylation in the presence of DYRK1B inhibitor. Therefore, these findings suggest that DYRK1B regulates CD4 T cell differentiation through FOXO1 phosphorylation and DYRK1B inhibitor has a potential as a novel agent for treatment of ACD.
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Dermatitis Alérgica por Contacto , Células Th17 , Animales , Ratones , Células Th17/patología , Inflamación , Linfocitos T CD4-Positivos/patología , Inmunosupresores/uso terapéutico , InmunidadRESUMEN
BACKGROUND: Cytokine-induced killer (CIK) cells are ex-vivo expanded T cells which present a phenotype of both T and Natural Killer cell properties. OBJECTIVE: To compare the proliferation and functional properties of human CIK cells cultured in three cell culture plasticwares. METHODS: The number and viability of CIK cells were monitored. The expression of surface markers (CD3 and CD56), TH1 cytokines (IFN-γ and TNF-α), and cytolytic granules (granzyme B and perforin) were determined by flow cytometry. RESULTS: The number of CIK cells cultured in a static bag was highest compared to those in a petri dish and gas-permeable flask. However, CIK cells cultured in all plasticwares similarity expressed surface marker, TH1 cytokines, and cytolytic granules. CONCLUSIONS: Considering safety, efficacy, and cost, a static bag is the best plasticware for culturing CIK cells.
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Células Asesinas Inducidas por Citocinas , Humanos , Células Cultivadas , Interferón gamma/metabolismo , Citocinas/metabolismo , Técnicas de Cultivo de CélulaRESUMEN
BACKGROUND: Cytokine-induced killer (CIK) cells are an ex vivo expanded heterogeneous population of natural killer (NK)-like T cells that can exert potent MHC-unrestricted antitumor activity. A number of pre-clinical and clinical studies have demonstrated that CIK cells can serve as a safe and potent immunotherapy of malignant tumors. N-acetylcysteine (NAC) has been demonstrated to enhance the T-cell functions by increasing their proliferation and cytokine production. OBJECTIVE: To investigate whether the incorporation of NAC to CIK cell culture could enhance the antitumor activity of CIK cells. METHODS: The phenotypes of human CIK cells, including CD3+CD56+, IFN-γ, granzyme B, and perforin, were determined by flow cytometry. The cytotoxic activity against the human erythroleukemic cell line (K562) and cholangiocarcinoma cell line (CL6) prelabeled with CFSE was investigated by flow cytometry. The mRNA expression levels of IFNG, PRF1, and GZMB were measured by real-time PCR. RESULTS: By adding NAC into CIK cell culture, the percentage of CD3+CD56+ cells along with the expression of Th1 cytokines and cytolytic granules increased significantly, resulting in an improvement of cytotoxicity against the cancer cell lines CL6 and K562. CONCLUSIONS: The incorporation of NAC into CIK culture can markedly improve the cytotoxicity against cancer cells due to the significant increase in the major effector population of CIK cells expressing Th1 cytokines and cytolytic granules.
RESUMEN
BACKGROUND: Long-term use of most immunosuppressants to treat allergic contact dermatitis (ACD) generates unavoidable severe side effects, warranting discovery or development of new immunosuppressants with good efficacy and low toxicity is urgently needed to treat this condition. Hispidulin, a flavonoid compound that can be delivered topically due to its favorable skin penetrability properties, has recently been reported to possess anti-inflammatory and immunosuppressive properties. However, no studies have investigated the effect of hispidulin on Th1 cell activities in an ACD setting. METHODS: A contact hypersensitivity (CHS) mouse model was designed to simulate human ACD. The immunosuppressive effect of hispidulin was investigated via ear thickness, histologic changes (i.e., edema and spongiosis), and interferon-gamma (IFN-γ) gene expression in 1-fluoro-2,4-dinitrobenzene (DNFB)-sensitized mice. Cytotoxicity, total number of CD4+ T cells, and percentage of IFN-γ-producing CD4+ T cells were also investigated in vitro using isolated CD4+ T cells from murine spleens. RESULTS: Topically applied hispidulin effectively inhibited ear swelling (as measured by reduction in ear thickness), and reduced spongiosis, IFN-γ gene expression, and the number of infiltrated immune cells. The inhibitory effect of hispidulin was observed within 6 h after the challenge, and the observed effects were similar to those effectuated after dexamethasone administration. Hispidulin at a concentration up to 50 µM also suppressed IFN-γ-producing CD4+ T cells in a dose-dependent manner without inducing cell death, and without a change in total frequencies of CD4+ T cells among different concentration groups. CONCLUSION: The results of this study, therefore, suggest hispidulin as a novel compound for the treatment of ACD via the suppression of IFN-γ production in Th1 cells.
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Dermatitis Alérgica por Contacto/tratamiento farmacológico , Flavonas/administración & dosificación , Inmunosupresores/administración & dosificación , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Dermatitis Alérgica por Contacto/genética , Dermatitis Alérgica por Contacto/inmunología , Modelos Animales de Enfermedad , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Células TH1/efectos de los fármacos , Células TH1/inmunologíaRESUMEN
AIM: To investigate the relationship between the levels of prostaglandin E2 (PGE2) in tears and dry eye disease severity based on both clinical symptoms and signs. METHODS: Tear samples were collected from 36 non-Sjögren syndrome dry eye patients (10 males and 26 females, mean age 50.11±11.17y). All participants completed the Ocular Surface Disease Index (OSDI) questionnaire and underwent a detailed ophthalmic examination including, tear film breakup time (TBUT), ocular surface fluorescein staining, Schirmer I test, and meibomian gland assessment. The level of PGE2 in tears was measured using enzyme-linked immunosorbent assay (ELISA). The independent associations between tear PGE2 levels and other variables including demographics, OSDI scores, TBUT, Schirmer scores, ocular surface staining scores, and stage of meibomian gland dysfunction (MGD) were evaluated using linear regression analysis. RESULTS: The mean PGE2 level in tears of dry eye patients was 537.85±234.02 pg/mL. The tear PGE2 levels significantly positively correlated with OSDI scores (R=0.608, P<0.001), however, they did not significantly associate with TBUT (R=0.153, P=0.373), Schirmer scores (R=-0.098, P=0.570), ocular surface staining scores (R=0.282, P=0.095), and stage of MGD (R=-0.107, P=0.535). Male sex was significantly negatively correlated with tear PGE2 levels. CONCLUSION: The levels of PGE2 in tears are positively correlated with dry eye symptoms. However, no significant association was found between tear PGE2 levels and the results of other common dry eye diagnostic tests.
RESUMEN
The effectiveness of cytokine-induced killer (CIK) cells for treatment of cancers has long been appreciated. Here, we report for the first time that CIK cells can be applied to treat allergic airway inflammation. Adopting from an established protocol with some modifications, we generated CIK cells ex vivo from mouse T cells, and examined their effectiveness in treatment of allergic airway inflammation using the ovalbumin-induced model of allergic airway inflammation. Based upon evaluation of bronchoalveolar lavage cellularity, T helper type2 cytokine levels and lung histology, all of which are important parameters for determining the severity of allergic airway inflammation, diseased mice treated with CIK cells showed significant reductions in all the parameters without any obvious adverse effects. Interestingly, the observed effects were comparable to those treated with dexamethasone. Thus, our study provides a novel application of CIK cells in treatment of allergic airway inflammation.
Asunto(s)
Asma/inmunología , Asma/terapia , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Células Asesinas Inducidas por Citocinas/citología , Hipersensibilidad/complicaciones , Animales , Asma/complicaciones , Asma/metabolismo , Citocinas/biosíntesis , Eosinófilos/inmunología , Células Caliciformes/patología , Hiperplasia , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Masculino , Ratones , Células TH1/citología , Células TH1/inmunologíaRESUMEN
OBJECTIVE: Cytokine induced killer (CIK) cells are ex-vivo expanded T cells endowed with both T and Natural Killer cell properties. The standard protocol for generation of CIK cells is to culture peripheral blood mononuclear cells (PBMC) in the presence of interferon- gamma (IFN-γ), monoclonal antibody (mAb) against CD3 and interleukin-2 (IL-2). However, this protocol lacks costimulatory signal (CD28), crucial for T cell activation. Herein, the proliferation and functional properties of murine thymocytes derived CIK cells generated with or without costimulatory activation provided by anti-CD28 mAb were examined. METHOD: The proportion of CIK (Thy1.2+NK1.1+ and CD8+NK1.1+) cells in culture and the expression of cytotoxic granules (granzyme B and perforin) and proinflammatory cytokines (IFN-γ and tumor necrosis factor-alpha (TNF-α)) were determined by flow cytometry. Additionally, CIK cell cytotoxicity against YAC-1 murine lymphoma cells was measured by a propidium iodide-based assay. RESULTS: The addition of anti-CD28 to standard CIK culture conditions increased the number of Thy1.2+ NK1.1+ and CD8+ NK1.1+ (the major effector population) cells by almost 40% and 32%, respectively. Furthermore, the cytotoxic potential of CIK cells cultured with the addition of anti-CD28 mAb was also enhanced, with a corresponding increase in CIK cells expressing granzyme B, perforin, IFN-γ and TNF-α. CONCLUSIONS: The addition of anti-CD28 mAb generated more effective murine T cell-derived CIK cells.
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Anticuerpos Monoclonales/farmacología , Antígenos CD28/inmunología , Linfocitos T CD8-positivos/inmunología , Células Asesinas Inducidas por Citocinas/inmunología , Citotoxicidad Inmunológica , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citometría de Flujo , Granzimas/metabolismo , Inmunofenotipificación , Interferón gamma/metabolismo , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Perforina/metabolismo , Transducción de Señal , Timocitos/citología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
UVA irradiation plays a role in premature aging of the skin through triggering oxidative stress-associated stimulation of matrix metalloproteinase-1 (MMP-1) responsible for collagen degradation, a hallmark of photoaged skin. Compounds that can activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor regulating antioxidant gene expression, should therefore serve as effective antiphotoaging agents. We investigated whether genetic silencing of Nrf2 could relieve UVA-mediated MMP-1 upregulation via activation of mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling using human keratinocyte cell line (HaCaT). Antiphotoaging effects of hispidulin (HPD) and sulforaphane (SFN) were assessed on their abilities to activate Nrf2 in controlling MMP-1 and collagen expressions in association with phosphorylation of MAPKs (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38), c-Jun, and c-Fos, using the skin of BALB/c mice subjected to repetitive UVA irradiation. Our findings suggested that depletion of Nrf2 promoted both mRNA expression and activity of MMP-1 in the UVA-irradiated HaCaT cells. Treatment of Nrf2 knocked-down HaCaT cells with MAPK inhibitors significantly suppressed UVA-induced MMP-1 and AP-1 activities. Moreover, pretreatment of the mouse skin with HPD and SFN, which could activate Nrf2, provided protective effects against UVA-mediated MMP-1 induction and collagen depletion in correlation with the decreased levels of phosphorylated MAPKs, c-Jun, and c-Fos in the mouse skin. In conclusion, Nrf2 could influence UVA-mediated MMP-1 upregulation through the MAPK/AP-1 signaling cascades. HPD and SFN may therefore represent promising antiphotoaging candidates.
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Colágeno/metabolismo , Flavonas/farmacología , Isotiocianatos/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Envejecimiento de la Piel , Rayos Ultravioleta/efectos adversos , Envejecimiento Prematuro/etiología , Envejecimiento Prematuro/metabolismo , Animales , Antimutagênicos/farmacología , Línea Celular , Activación Enzimática/efectos de la radiación , Humanos , Queratinocitos , Sistema de Señalización de MAP Quinasas/efectos de la radiación , Metaloproteinasa 1 de la Matriz/metabolismo , Ratones , Estrés Oxidativo , Piel/metabolismo , Envejecimiento de la Piel/efectos de los fármacos , Envejecimiento de la Piel/efectos de la radiación , Sulfóxidos , Factor de Transcripción AP-1/metabolismo , Regulación hacia Arriba/efectos de la radiaciónRESUMEN
UNLABELLED: Hepatic stellate cells (HSCs) constitute the liver sinusoid with Kupffer cells and liver sinusoidal endothelial cells. While the sinusoid functions as the gateway to liver inflammation, whether HSCs contribute to liver inflammation and, if so, how they exert such functions remain elusive. Here, we found that mouse as well as human HSCs expressed DP1 receptor for prostaglandin D2 selectively in the liver. Pharmacological stimulation of DP1 by BW245C, a DP1-selective agonist, suppressed the activation of cultured HSCs by tumor necrosis factor-α at least in part through down-regulation of nuclear factor kappa-light-chain-enhancer of activated B cells signaling and inhibition of c-Jun N-terminal kinase phosphorylation. DP1 deficiency or BW245C administration in mice significantly enhanced or suppressed concanavalin A (ConA)-induced hepatitis, respectively. ConA injection induced tumor necrosis factor-α and interferon-γ expression in the sinusoid, which was suppressed by administration of BW245C. Coculture of spleen cells and liver nonparenchymal cells showed that ConA first activated spleen cells and that this activation led to activation of nonparenchymal cells to secondarily produce tumor necrosis factor-α and interferon-γ. Microarray analysis revealed ConA-induced expression of endothelin-1, tissue factor, and chemokines in the liver and inducible nitric oxide synthase in hepatocytes, resulting in flow stagnation, leukocyte adherence and migration to the parenchyma, and hepatocyte death. DP1 stimulation inhibits all these events in the liver. Therefore, HSCs mediate amplification of ConA-induced liver inflammation in the sinusoid, causing direct and indirect hepatocyte injury, and DP1 stimulation inhibits this HSC activation. CONCLUSIONS: HSCs integrate cytokine-mediated inflammatory responses in the sinusoids and relay them to the liver parenchyma, and these HSC actions are inhibited by DP1 stimulation.
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Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Concanavalina A/farmacología , Células Estrelladas Hepáticas/metabolismo , Hepatitis C/inmunología , Hepatitis C/patología , Animales , Biopsia con Aguja , Estudios de Casos y Controles , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Quimiocinas/efectos de los fármacos , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Hepatitis C/fisiopatología , Humanos , Inmunohistoquímica , Interferón gamma/metabolismo , Macrófagos del Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Distribución Aleatoria , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Valores de Referencia , Sensibilidad y Especificidad , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Pollen allergy is a growing global health issue. While airborne pollen counts are reported daily in several countries, such information is lacking in Thailand. OBJECTIVE: This study aimed to survey airborne pollens at five sites in Bangkok, comparing data with the previous study performed 35 years ago in 1980. METHODS: Sample collection was done using the ROTOROD® sampler by exposing the rods for one hour each day twice a week from May 2012-April 2013. RESULTS: Overall, we found that the average pollen count was relatively high throughout the year, at an average of 242 grains/m3. The highest peak was found in September (700 grains/m3). Interestingly, we found that the pollen count was noticeably lower in 2012-2013 when compared to the 1980 study. We also observed the approximate shift of pollen peaks about one to two months earlier in the 2012-2013 study. However, the major groups of airborne pollens did not change significantly. Grass, sedge, amaranthus pollens and fern spores still dominated. The unidentified pollen group was the only group with a higher pollen count when compared to the previous study.
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Exposición a Riesgos Ambientales/efectos adversos , Monitoreo del Ambiente/métodos , Polen/efectos adversos , Rinitis Alérgica Estacional/epidemiología , Salud Urbana , Encuestas Epidemiológicas , Humanos , Rinitis Alérgica Estacional/diagnóstico , Estaciones del Año , Tailandia/epidemiología , Factores de TiempoRESUMEN
T helper 1 (Th1) cells have critical roles in various autoimmune and proinflammatory diseases. cAMP has long been believed to act as a suppressor of IFN-γ production and Th1 cell-mediated immune inflammation. Here we show that cAMP actively promotes Th1 differentiation by inducing gene expression of cytokine receptors involved in this process. PGE2 signalling through EP2/EP4 receptors mobilizes the cAMP-PKA pathway, which induces CREB- and its co-activator CRTC2-mediated transcription of IL-12Rß2 and IFN-γR1. Meanwhile, cAMP-mediated suppression of T-cell receptor signalling is overcome by simultaneous activation of PI3-kinase through EP2/EP4 and/or CD28. Loss of EP4 in T cells restricts expression of IL-12Rß2 and IFN-γR1, and attenuates Th1 cell-mediated inflammation in vivo. These findings clarify the molecular mechanisms and pathological contexts of cAMP-mediated Th1 differentiation and have clinical and therapeutic implications for deployment of cAMP modulators as immunoregulatory drugs.
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Diferenciación Celular/fisiología , AMP Cíclico/fisiología , Dinoprostona/fisiología , Interleucina-12/metabolismo , Fosfatidilinositol 3-Quinasas/fisiología , Transducción de Señal/fisiología , Células TH1/citología , Animales , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/fisiologíaRESUMEN
UV radiation induces systemic immunosuppression. Because nonsteroidal anti-inflammatory drugs suppress UV-induced immunosuppression, prostanoids have been suspected as a crucial mediator of this UV effect. However, the identity of the prostanoid involved and its mechanism of action remain unclear. Here, we addressed this issue by subjecting mice deficient in each prostanoid receptor individually or mice treated with a subtype-specific antagonist to UV irradiation. Mice treated with an antagonist for prostaglandin E receptor subtype 4 (EP4), but not those deficient in other prostanoid receptors, show impaired UV-induced immunosuppression, whereas administration of an EP4 agonist rescues the impairment of the UV-induced immunosuppression in indomethacin-treated mice. The EP4 antagonist treatment suppresses an increase in the number of CD4(+)/forkhead box P3-positive (Foxp3(+)) regulatory T cells (Treg cells) in the peripheral lymph nodes (LNs) and dendritic cells expressing DEC205 in the LNs and the skin after UV irradiation. Furthermore, the EP4 antagonist treatment down-regulates UV-induced expression of receptor activator of NF-κB ligand (RANKL) in skin keratinocytes. Finally, administration of anti-RANKL antibody abolishes the restoration of UV-induced immunosuppression by EP4 agonism in indomethacin-treated mice. Thus, prostaglandin E(2) (PGE(2))-EP4 signaling mediates UV-induced immunosuppression by elevating the number of Treg cells through regulation of RANKL expression in the epidermis.
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Dinoprostona/inmunología , Tolerancia Inmunológica/efectos de la radiación , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP4 de Receptores de Prostaglandina E/inmunología , Rayos Ultravioleta/efectos adversos , Animales , Antiinflamatorios no Esteroideos/farmacología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Dinoprostona/genética , Dinoprostona/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Regulación de la Expresión Génica/efectos de la radiación , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Indometacina/farmacología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ratones , Ratones Transgénicos , Ligando RANK/biosíntesis , Ligando RANK/genética , Ligando RANK/inmunología , Subtipo EP4 de Receptores de Prostaglandina E/genética , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
Prostaglandin E2 (PGE2) exerts its actions via four subtypes of the PGE receptor, EP1-4. We show that mice deficient in EP1 exhibited significantly attenuated Th1 response in contact hypersensitivity induced by dinitrofluorobenzene (DNFB). This phenotype was recapitulated in wild-type mice by administration of an EP1-selective antagonist during the sensitization phase, and by adoptive transfer of T cells from sensitized EP1-/- mice. Conversely, an EP1-selective agonist facilitated Th1 differentiation of naive T cells in vitro. Finally, CD11c+ cells containing the inducible form of PGE synthase increased in number in the draining lymph nodes after DNFB application. These results suggest that PGE2 produced by dendritic cells in the lymph nodes acts on EP1 in naive T cells to promote Th1 differentiation.