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1.
BMC Complement Altern Med ; 19(1): 268, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615568

RESUMO

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.


Assuntos
Dermatite Alérgica de Contato/tratamento farmacológico , Flavonas/administração & dosagem , Imunossupressores/administração & dosagem , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Dermatite Alérgica de Contato/genética , Dermatite Alérgica de Contato/imunologia , Modelos Animais de Doenças , Humanos , Interferon gama/genética , Interferon gama/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/efeitos dos fármacos , Células Th1/imunologia
2.
Int J Ophthalmol ; 12(7): 1127-1133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341803

RESUMO

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.

3.
PLoS One ; 12(10): e0186971, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29073213

RESUMO

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.


Assuntos
Asma/imunologia , Asma/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Matadoras Induzidas por Citocinas/citologia , Hipersensibilidade/complicações , Animais , Asma/complicações , Asma/metabolismo , Citocinas/biossíntese , Eosinófilos/imunologia , Células Caliciformes/patologia , Hiperplasia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Células Th1/citologia , Células Th1/imunologia
4.
Asian Pac J Allergy Immunol ; 35(2): 67-74, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27543727

RESUMO

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.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos CD28/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Matadoras Induzidas por Citocinas/imunologia , Citotoxicidade Imunológica , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citometria de Fluxo , Granzimas/metabolismo , Imunofenotipagem , Interferon gama/metabolismo , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Perforina/metabolismo , Transdução de Sinais , Timócitos/citologia , Fator de Necrose Tumoral alfa/metabolismo
5.
J Pharmacol Exp Ther ; 360(3): 388-398, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28011874

RESUMO

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.


Assuntos
Colágeno/metabolismo , Flavonas/farmacologia , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Envelhecimento da Pele , Raios Ultravioleta/efeitos adversos , Senilidade Prematura/etiologia , Senilidade Prematura/metabolismo , Animais , Antimutagênicos/farmacologia , Linhagem Celular , Ativação Enzimática/efeitos da radiação , Humanos , Queratinócitos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Estresse Oxidativo , Pele/metabolismo , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Fator de Transcrição AP-1/metabolismo , Regulação para Cima/efeitos da radiação
6.
Hepatology ; 63(4): 1325-39, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26248612

RESUMO

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.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A/farmacologia , Células Estreladas do Fígado/metabolismo , Hepatite C/imunologia , Hepatite C/patologia , Animais , Biópsia por Agulha , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Quimiocinas/efeitos dos fármacos , Quimiocinas/metabolismo , Modelos Animais de Doenças , Feminino , Hepatite C/fisiopatologia , Humanos , Imuno-Histoquímica , Interferon gama/metabolismo , Macrófagos do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real/métodos , Valores de Referência , Sensibilidade e Especificidade , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
7.
Asian Pac J Allergy Immunol ; 33(3): 253-62, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26342123

RESUMO

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.


Assuntos
Exposição Ambiental/efeitos adversos , Monitoramento Ambiental/métodos , Pólen/efeitos adversos , Rinite Alérgica Sazonal/epidemiologia , Saúde da População Urbana , Inquéritos Epidemiológicos , Humanos , Rinite Alérgica Sazonal/diagnóstico , Estações do Ano , Tailândia/epidemiologia , Fatores de Tempo
8.
Nat Commun ; 4: 1685, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23575689

RESUMO

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.


Assuntos
Diferenciação Celular/fisiologia , AMP Cíclico/fisiologia , Dinoprostona/fisiologia , Interleucina-12/metabolismo , Fosfatidilinositol 3-Quinases/fisiologia , Transdução de Sinais/fisiologia , Células Th1/citologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/fisiologia
9.
Proc Natl Acad Sci U S A ; 108(16): 6668-73, 2011 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-21460251

RESUMO

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.


Assuntos
Dinoprostona/imunologia , Tolerância Imunológica/efeitos da radiação , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/imunologia , Raios Ultravioleta/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Dinoprostona/genética , Dinoprostona/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Regulação da Expressão Gênica/efeitos da radiação , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Indometacina/farmacologia , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos , Camundongos Transgênicos , Ligante RANK/biossíntese , Ligante RANK/genética , Ligante RANK/imunologia , Receptores de Prostaglandina E Subtipo EP4/genética , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
10.
J Exp Med ; 204(12): 2865-74, 2007 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-17967902

RESUMO

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.


Assuntos
Receptores de Prostaglandina E/imunologia , Células Th1/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Diferenciação Celular , Cinamatos/farmacologia , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Dinoprostona/fisiologia , Linfonodos/imunologia , Linfonodos/fisiologia , Camundongos , Camundongos Knockout , Prostaglandinas/fisiologia , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/deficiência , Receptores de Prostaglandina E Subtipo EP1 , Subpopulações de Linfócitos T/imunologia , Células Th1/citologia , Células Th2/imunologia
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