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1.
Food Chem ; 305: 125438, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494498

RESUMO

Fifteen vitisin A-type pyranoanthocyanins (vAPs) were determined in bilberry wines fermented with Saccharomyces cerevisiae and Schizosaccharomyces pombe by HPLC-DAD and UPLC-DAD-ESI-MS/MS. The fermentation involving S. pombe enhanced the production of vAPs compared to the fermentation with pure S. cerevisiae. The formation of vAPs correlated significantly with the decrease in the content of monomeric anthocyanins and pyruvic acid during 12 months of aging. vAPs were more stable than their corresponding monomeric anthocyanins. Methylation in the B-ring and glycosylation with galactose and arabinose further improved the stability of vAPs. Aging for 12 months led to depletion of pyruvic acid and reduction of over 50% of monomeric anthocyanins. The content of vAPs increased by 26-54% during the first six months of aging, followed by a 2.2-10.2% reduction over the following six months. More residual pyruvic acid in S. pombe wines after fermentation consequently enhanced the generation of vAPs during aging.

2.
Cell Mol Immunol ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772283

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

3.
Comput Methods Programs Biomed ; : 105099, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31601442

RESUMO

OBJECTIVE: Understanding the three-dimensional (3D) spatial position and orientation of vessels and tumor(s) is vital in laparoscopic liver resection procedures. Augmented reality (AR) techniques can help surgeons see the patient's internal anatomy in conjunction with laparoscopic video images. METHOD: In this paper, we present an AR-assisted navigation system for liver resection based on a rigid stereoscopic laparoscope. The stereo image pairs from the laparoscope are used by an unsupervised convolutional network (CNN) framework to estimate depth and generate an intraoperative 3D liver surface. Meanwhile, 3D models of the patient's surgical field are segmented from preoperative CT images using V-Net architecture for volumetric image data in an end-to-end predictive style. A globally optimal iterative closest point (Go-ICP) algorithm is adopted to register the pre- and intraoperative models into a unified coordinate space; then, the preoperative 3D models are superimposed on the live laparoscopic images to provide the surgeon with detailed information about the subsurface of the patient's anatomy, including tumors, their resection margins and vessels. RESULTS: The proposed navigation system is tested on four laboratory ex vivo porcine livers and five operating theatre in vivo porcine experiments to validate its accuracy. The ex vivo and in vivo reprojection errors (RPE) are 6.04 ±â€¯1.85 mm and 8.73 ±â€¯2.43 mm, respectively. CONCLUSION AND SIGNIFICANCE: Both the qualitative and quantitative results indicate that our AR-assisted navigation system shows promise and has the potential to be highly useful in clinical practice.

4.
Immunity ; 50(3): 600-615.e15, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30824325

RESUMO

CCR7 chemokine receptor stimulation induces rapid but transient dendritic cell (DC) migration toward draining lymph nodes, which is critical for the initiation of protective immunity and maintenance of immune homeostasis. The mechanisms for terminating CCR7-mediated DC migration remain incompletely understood. Here we have identified a long non-coding RNA lnc-Dpf3 whose feedback restrained CCR7-mediated DC migration. CCR7 stimulation upregulated lnc-Dpf3 via removing N6-methyladenosine (m6A) modification to prevent RNA degradation. DC-specific lnc-Dpf3 deficiency increased CCR7-mediated DC migration, leading to exaggerated adaptive immune responses and inflammatory injuries. Mechanistically, CCR7 stimulation activated the HIF-1α transcription factor pathway in DCs, leading to metabolic reprogramming toward glycolysis for DC migration. lnc-Dpf3 directly bound to HIF-1α and suppressed HIF-1α-dependent transcription of the glycolytic gene Ldha, thus inhibiting DC glycolytic metabolism and migratory capacity. We demonstrate a critical role for CCR7-inducible lnc-Dpf3 in coupling epigenetic and metabolic pathways to feedback-control DC migration and inflammatory responses.


Assuntos
Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Glicólise/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Receptores CCR7/genética , Fatores de Transcrição/genética , Imunidade Adaptativa/genética , Animais , Linhagem Celular , Células Dendríticas/patologia , Epigênese Genética/genética , Regulação da Expressão Gênica/genética , Células HEK293 , Humanos , Inflamação/genética , Inflamação/patologia , Linfonodos/patologia , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Endogâmicos C57BL , Transcrição Genética/genética , Regulação para Cima/genética
5.
Food Microbiol ; 80: 25-39, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30704594

RESUMO

Bilberry (Vaccinium myrtillus L.) juice was fermented with Torulaspora delbrueckii (TD291 and TD70526) and Schizosaccharomyces pombe (SP3796 and SP70572) in pure fermentation as well as in sequential and simultaneous inoculations with Saccharomyces cerevisiae 1116 (SC1116). Altogether, 56 volatile compounds were identified and semi-quantified with HS-SPME-GC/MS in bilberry products. Yeast fermentation prominently enhanced the aroma complexity of bilberry with a sharp increase in alcohols, esters, aldehydes, and acetals. Compared to S. cerevisiae, T. delbrueckii produced less ethanol but more fusel alcohols that potentially enhance "alcohol" and "nail polish" odors in TD70526 and less "fruity" esters in TD291. SP70572 resulted in high productions of undesirable compounds of acetoin and acetaldehyde but a low content of higher alcohols and esters, SP3796 produced a high content of fatty acid ethyl esters and acetoin. In comparison with monoculture of non-Saccharomyces yeast, sequential and simultaneous cultures of S. pombe and S. cerevisiae significantly decreased the content of acetoin while increased the relative level of esters; sequential cultures of T. delbrueckii and S. cerevisiae remarkably increased the concentration of acetaldehyde; simultaneous inoculations of S. cerevisiae with TD70526 and TD291 significantly decreased the content of fusel alcohols and increased the content of esters, respectively. The findings suggested that non-Saccharomyces yeasts possess the potential to affect and modulate the aromatic profile of fermented bilberry products. Sequential and simultaneous inoculations with S. pombe strains and S. cerevisiae as well as simultaneous fermentation using T. delbrueckii strains and S. cerevisiae are optimal strategies to positively influence the aroma profile of bilberry wines.


Assuntos
Saccharomyces cerevisiae/metabolismo , Schizosaccharomyces/metabolismo , Torulaspora/metabolismo , Vaccinium myrtillus/metabolismo , Compostos Orgânicos Voláteis/análise , Vinho/análise , Antocianinas/metabolismo , Técnicas de Cocultura , Fermentação , Cinética , Vinho/microbiologia
6.
Cell Mol Immunol ; 2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635648

RESUMO

Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors. However, the epigenetic mechanisms that regulate human dendritic cell (DC) differentiation and development remain poorly understood. Our previous studies show that extracellular heat shock protein 70-like protein (HSP70L1) is a potent adjuvant of Th1 responses via stimulating DCs when released from cells; however, the role of intracellular HSP70L1 in DC differentiation and maturation remains unknown. Herein, we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression, in contrast to the adjuvant activity of extracellular HSP70L1. The stability of intracellular HSP70L1 is dependent on DNAJC2, a known epigenetic regulator. Mechanistically, intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory, MHC and STAT3 genes. Thus, intracellular HSP70L1 is an inhibitor of human DC maturation. Our results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.

7.
Food Chem ; 266: 262-274, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30381185

RESUMO

This study evaluated the effects of fermentation with pure cultures of Torulaspora delbrueckii (TD291 and TD70526) and Schizosaccharomyces pombe (SP3796 and SP70572), as well as in sequential and mixed inoculations with Saccharomyces cerevisiae, on the chemical composition of bilberry wine. In comparison to the bilberry wines produced by pure and sequential fermentations, mixed cultures produced bilberry wines with more ethanol, higher pH values, higher percentages of red and yellow shade, but less glycerol and acetaldehyde. Higher values of color intensity and bluish parameter were found in products of pure fermentations with non-Saccharomyces yeasts. Compared to S. cerevisiae, T. delbrueckii contributed to the reduction of ethanol and acetic acid while increasing the content of succinic acid, lactic acid and higher alcohols; S. pombe consumed malic acid almost completely and produced more glycerol, acetaldehyde and/or pyruvic acid. Fermentation with SP70572 had the highest amounts of anthocyanins and hydroxycinnamic acids derivatives.

8.
Immunity ; 49(4): 640-653.e5, 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332630

RESUMO

Tissue-resident mast cells are associated with many inflammatory and physiological processes. Although mast cells arise from the yolk sac, the exact ontogeny of adult mast cells remains unclear. Here we have investigated the hematopoietic origin of mast cells using fate-mapping systems. We have shown that early erythro-myeloid progenitors (EMPs), late EMPs, and definitive hematopoietic stem cells (HSCs) each gave rise to mast cells in succession via an intermediate integrin ß7+ progenitor. From late embryogenesis to adult, early EMP-derived mast cells were largely replaced by late EMP-derived cells in most connective tissues except adipose and pleural cavity. Thus, mast cells with distinct origin displayed tissue-location preferences: early EMP-derived cells were limited to adipose and pleural cavity and late EMP-derived cells dominated most connective tissues, while HSC-derived cells were a main group in mucosa. Therefore, embryonic origin shapes the heterogeneity of adult mast cells, with diverse functions in immunity and development.

9.
J Food Sci Technol ; 55(6): 2240-2250, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29892124

RESUMO

This study aimed to investigate the effect of Lactobacillus plantarum strains on quality improvement of bog bilberry juice. Bog bilberry juice with different pH conditions was fermented by Lactobacillus B7 or C8-1 strain. Physicochemical index, amino acids, phenolic compounds, and volatiles of these fermented juices were compared. Results indicated that Lactobacillus plantarum strains preferred to metabolize malic acid and reducing sugar in non-pH-adjusted juice (NJ, pH 2.65), whereas quinic and citric acids were largely consumed in pH-adjusted juice (AJ, pH 3.50). Shikimic acid and aromatic amino acids were significantly accumulated in pH-adjusted juice, and phenolic compounds in both juices were significantly reduced. These strains enhanced the composition and concentration of volatiles compounds in non-pH-adjusted juice and improved the floral and fruity flavors. However, concentration and complexity of volatiles were reduced in pH-adjusted juices.

10.
Cell Mol Immunol ; 15(8): 768-781, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29375131

RESUMO

We previously identified human phosphatidylethanolamine-binding protein 4 (hPEBP4) as an antiapoptotic protein with increased expression levels in breast, ovarian and prostate cancer cells, but low expression levels in normal tissues, which makes hPEBP4 an attractive target for immunotherapy. Here, we developed hPEBP4-derived immunogenic peptides for inducing antigen-specific cytotoxic T lymphocytes (CTLs) targeting breast cancer. A panel of hPEBP4-derived peptides predicted by peptide-MHC-binding algorithms was evaluated to characterize their HLA-A2.1 affinity and immunogenicity. We identified a novel immunogenic peptide, P40-48 (TLFCQGLEV), that was capable of eliciting specific CTL responses in HLA-A2.1/Kb transgenic mice, as well as in peripheral blood lymphocytes from breast cancer patients. Furthermore, amino-acid substitutions in the P40-48 sequence improved its immunogenicity against hPEBP4, a self-antigen, thus circumventing tolerance. We designed peptide analogs by preferred auxiliary HLA-A*0201 anchor residue replacement, which induced CTLs that were crossreactive to the native peptide. Several analogs were able to stably bind to HLA-A*0201 and elicit specific CTL responses better than the native sequence. Importantly, adoptive transfer of CTLs induced by vaccination with two analogs more effectively inhibited tumor growth than the native peptide. These data indicate that peptide analogs with high immunogenicity represent promising candidates for peptide-mediated therapeutic cancer vaccines.

11.
Cell Mol Immunol ; 15(2): 135-145, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27345726

RESUMO

Heat-shock protein (HSP)-based immunotherapy is established on its adjuvant effects when applied via an extracellular approach to pulse and activate dendritic cells (DCs). Our previous studies indicate that DCs pulsed with recombinant fusion proteins of antigenic fragment and HSP70-like protein 1 (HSP70L1) are potent in stimulating antigen-specific Th1 responses. We herein evaluated the cytotoxic T cell (CTL) response by an intracellular approach of priming DCs with transfection of recombinant adenovirus-expressing the fusion gene of the 576-699 fragment of carcinoembryonic antigen (CEA) and HSP70L1. As compared with DCs pulsed with extracellular fusion protein, the DCs transfected with recombinant adenovirus expressing the fusion gene displayed equivalent mature phenotypes but less inflammatory appearance. However, the transfected DCs were superior to the pulsed DCs in inducing CEA-specific CTLs. Consistently, immunization of HLA-A2.1/H-2Kb transgene mice with the transfected DCs could induce more quantities of HLA-A2.1-restricted CEA-specific CTLs, protecting nude mice more significantly from human CEA-expressing colon tumor challenge when adoptively transferred. Mechanistic investigation indicated that intracellular expression of the fusion protein empowered the transfected DCs by activation of STAT1 possibly via inducing IFN-ß and ERK pathways. Therefore, the more potent ability to induce anti-CEA CTL responses enables the DCs, which transfected with recombinant adenovirus expressing the fusion gene of antigenic CEA fragment and Th1 adjuvant, as an alternative promising approach for the immunotherapy of CEA-positive tumors.

12.
Cell ; 170(3): 492-506.e14, 2017 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-28753426

RESUMO

Interferon-α (IFNα) signaling is essential for antiviral response via induction of IFN-stimulated genes (ISGs). Through a non-biased high-throughput RNAi screening of 711 known epigenetic modifiers in cellular models of IFNα-mediated inhibition of HBV replication, we identified methyltransferase SETD2 as a critical amplifier of IFNα-mediated antiviral immunity. Conditional knockout mice with hepatocyte-specific deletion of Setd2 exhibit enhanced HBV infection. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response. In addition, SETD2 selectively catalyzes the tri-methylation of H3K36 on promoters of some ISGs such as ISG15, leading to gene activation. Our study identifies STAT1 methylation on K525 catalyzed by the methyltransferase SETD2 as an essential signaling event for IFNα-dependent antiviral immunity and indicates potential of SETD2 in controlling viral infections.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B Crônica/imunologia , Histona-Lisina N-Metiltransferase/metabolismo , Interferon-alfa/imunologia , Fator de Transcrição STAT1/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Epigênese Genética , Hepatite B Crônica/virologia , Hepatócitos/metabolismo , Histonas/metabolismo , Humanos , Camundongos , Fosforilação , Domínios Proteicos , Interferência de RNA , Transcrição Genética , Replicação Viral
13.
Nat Commun ; 8: 15818, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28598443

RESUMO

Regulatory T (Treg) cells are important for the maintenance of immune homoeostasis and prevention of autoimmune diseases. Epigenetic modifications have been reported to modulate autoimmunity by altering Treg cell fate. Here we show that the H3K4 methyltransferase Ash1l facilitates TGF-ß-induced Treg cell polarization in vitro and protects mice from T cell-mediated colitis in vivo. Ash1l upregulates Smad3 expression by directly targeting Smad3 promoter to increase local H3K4 trimethylation. Furthermore, we identify an lncRNA, namely lnc-Smad3, which interacts with the histone deacetylase HDAC1 and silences Smad3 transcription. After TGF-ß stimulation, activated Smad3 suppresses lnc-Smad3 transcription, thereby recovering the Smad3 promoter accessibility to Ash1l. By revealing the opposite regulatory functions of Ash1l and lnc-Smad3 in Smad3 expression, our data provide insights for the epigenetic control of Treg cell fate to potentially aid in the development of therapeutic intervention for autoimmune diseases.

14.
J Food Sci ; 81(11): C2697-C2707, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27755647

RESUMO

This study investigated the evolution of phenolic compounds of bog bilberry syrup wine during a bottle-aging process, and further estimated the oak chip treatment on the wine color alteration. The wine was macerated with oak chips (2 or 5 g/L under light or medium toasting level) for 20 d and then bottle-aged for 6 mo. Results showed that the oak chip treatment significantly increased the content of phenolic compounds and enhanced the copigmented anthocyanin level before aging. It also resulted in an increase on a* and C* but a decrease on L* , b* , and H* of the wine. During aging process, a content decrease of total phenol and antioxidant capacity of the wine was observed. Phenolic acids, flavonol glycosides, and anthocyanins reduced the content, whereas flavonol increased the content. Free and copigmented anthocyanin levels decreased, whereas polymerized anthocyanins level increased. This process caused an increase on L* , b* , and H* , but a decrease on a* and C* . The oak chip treatment delayed the wine color change and its effect was mainly depended on the addition amount. Partial least square regression revealed that flavonol glycosides, phenolic acids, and anthocyanins displayed a positive correlation with L* , b* , and H* , but a negative correlation with a* and C* . Quercetin-3-O-glucuronide, myricetin-3-O-galactoside, chlorogenic acid, and quercetin exerted a more important effect on the color alteration in wine.

15.
Molecules ; 20(11): 19865-77, 2015 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-26556321

RESUMO

Phenolic compounds determine the color quality of fruit wines. In this study, the phenolic compound content and composition, color characteristics and changes during 6 months of bottle aging were studied in wines fermented with bog bilberry syrup under three different pHs. The total anthocyanins and total phenols were around 15.12-16.23 mg/L and 475.82 to 486.50 mg GAE/L in fresh wines and declined 22%-31% and about 11% in bottle aged wines, respectively. In fresh wines, eight anthocyanins, six phenolic aids and 14 flavonols, but no flavon-3-ols were identified; Malvidin-3-O-glucoside, petunidin-3-O-glucoside and delphinium-3-O-glucoside were the predominant pigments; Chlorogentic acid was the most abundant phenolic acid, and quercetin-3-O-galactoside and myricetin-3-O-galactoside accounted for nearly 90% of the total flavonols. During 6 months of bottle storage, the amounts of all the monomeric anthocyanins and phenolic acids were reduced dramatically, while the glycosidyl flavonols remained constant or were less reduced and their corresponding aglycones increased a lot. The effects of aging on blueberry wine color were described as the loss of color intensity with a dramatic change in color hue, from initial red-purple up to final red-brick nuances, while the pH of the fermentation matrix was negatively related to the color stability of aged wine.


Assuntos
Polifenóis/química , Vaccinium myrtillus/química , Vinho/análise , Antocianinas/química , Fermentação , Flavonóis/química , Concentração de Íons de Hidrogênio , Hidroxibenzoatos/química , Fenóis/química , Pigmentos Biológicos/análise
16.
Nat Immunol ; 15(7): 612-22, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24859449

RESUMO

Excessive activation of dendritic cells (DCs) leads to the development of autoimmune and inflammatory diseases, which has prompted a search for regulators of DC activation. Here we report that Rhbdd3, a member of the rhomboid family of proteases, suppressed the activation of DCs and production of interleukin 6 (IL-6) triggered by Toll-like receptors (TLRs). Rhbdd3-deficient mice spontaneously developed autoimmune diseases characterized by an increased abundance of the TH17 subset of helper T cells and decreased number of regulatory T cells due to the increase in IL-6 from DCs. Rhbdd3 directly bound to Lys27 (K27)-linked polyubiquitin chains on Lys302 of the modulator NEMO (IKKγ) via the ubiquitin-binding-association (UBA) domain in endosomes. Rhbdd3 further recruited the deubiquitinase A20 via K27-linked polyubiquitin chains on Lys268 to inhibit K63-linked polyubiquitination of NEMO and thus suppressed activation of the transcription factor NF-κB in DCs. Our data identify Rhbdd3 as a critical regulator of DC activation and indicate K27-linked polyubiquitination is a potent ubiquitin-linked pattern involved in the control of autoimmunity.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Autoimunidade , Células Dendríticas/imunologia , Interleucina-6/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ubiquitinação , Animais , Interleucina-6/antagonistas & inibidores , Lisina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/fisiologia , Estrutura Terciária de Proteína , Linfócitos T/imunologia , Receptores Toll-Like/fisiologia
17.
Immunity ; 39(3): 470-81, 2013 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-24012418

RESUMO

Histone modifications play important roles in multiple physiological processes by regulating gene expression. However, the roles of histone modifications in immunity remain poorly understood. Here we report that Ash1l, a H3K4 methyltransferase, suppressed interleukin-6 (IL-6), and tumor necrosis factor (TNF) production in Toll-like receptor (TLR)-triggered macrophages, protecting mice from sepsis. Ash1l-silenced mice were more susceptible to autoimmune disease as a result of enhanced IL-6 production. Ash1l enhanced A20 expression through induction of H3K4 modification at the Tnfaip3 promoter via H3K4 methyltransferase activity of Ash1l SET (Su[var]3-9, E[z] and trithorax) domain. Ash1l suppressed NF-κB, mitogen-activated protein kinase (MAPK) pathways, and subsequent IL-6 production via facilitating A20-mediated NF-κB signal modulator NEMO and transducer TRAF6 deubiquitination. Therefore, Ash1l-mediated H3K4 methylation at the Tnfaip3 promoter is required for controlling innate IL-6 production and suppressing inflammatory autoimmune diseases, providing mechanistic insight into epigenetic modulation of immune responses and inflammation.


Assuntos
Doenças Autoimunes/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Interleucina-6/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Cultivadas , Cisteína Endopeptidases , Proteínas de Ligação a DNA/biossíntese , Histonas/metabolismo , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Inflamação , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Macrófagos , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno , Sepse/imunologia , Sepse/prevenção & controle , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Receptores Toll-Like/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Fatores de Necrose Tumoral/biossíntese , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/biossíntese
18.
Proc Natl Acad Sci U S A ; 110(19): 7814-9, 2013 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-23610400

RESUMO

Rhomboid domain-containing protein 3 (Rhbdd3), which belongs to a family of proteins with rhomboid domain, is widely expressed in immune cells; however, the roles of the Rhbdd members, including Rhbdd3, in immunity remain unknown. Natural killer (NK) cells are critical for host immune defense and also can mediate inflammatory diseases such as hepatitis. Although much is known about how NK cells are activated, the detailed mechanisms for negative regulation of NK cell activation remain to be fully understood. Using Rhbdd3-deficient mice, we reveal that Rhbdd3, selectively up-regulated in NK cells upon Toll-like receptor 3 (TLR3) stimulation, negatively regulates TLR3-mediated NK cell activation in a feedback manner. Rhbdd3 inhibits TLR3-triggered IFN-γ and granzyme B expression of NK cells in cell-cell contact dependence of accessory cells such as dendritic cells and Kupffer cells. Rhbdd3 interacts with DNAX activation protein of 12 kDa and promotes its degradation, inhibiting MAPK activation in TLR3-triggered NK cells. Furthermore, Rhbdd3 plays a critical role in attenuating TLR3-triggered acute inflammation by controlling NK cell activation and accumulation in liver and disrupting NK cell-Kupffer cell interaction. Therefore, Rhbdd3 is a feedback inhibitor of TLR3-triggered NK cell activation. Our study outlines a mechanism for the negative regulation of NK cell activation and also provides clues for the function of the rhomboid proteins in immunity.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Regulação da Expressão Gênica , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Receptor 3 Toll-Like/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Comunicação Celular , Células Dendríticas/citologia , Ensaio de Imunoadsorção Enzimática , Macrófagos do Fígado/citologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Poli I-C/metabolismo , Interferência de RNA , Regulação para Cima
19.
J Neuroimmunol ; 255(1-2): 32-8, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23200567

RESUMO

The abnormal proliferation and polarization of Th17/Th1 subsets are believed to contribute to the progression of multiple sclerosis. We demonstrated that neural stem cells (NSCs) could inhibit CD4(+)T cells from mice of experimental autoimmune encephalomyelitis to proliferate and polarize into Th17 but promote their apoptosis and to generate regulatory T cells in response to myelin antigen via releasing prostaglandin E2 by activated Th1-derived IFN-γ. The study indicated that NSCs play a negatively regulatory role in T cell responses and provided novel evidence for the therapeutic mechanisms underlying the usage of NSCs to treat autoimmune diseases of central nervous system.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Dinoprostona/fisiologia , Células-Tronco Embrionárias/imunologia , Bainha de Mielina/imunologia , Células-Tronco Neurais/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Células Cultivadas , Técnicas de Cocultura , Células-Tronco Embrionárias/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Bainha de Mielina/patologia , Células-Tronco Neurais/metabolismo , Gravidez
20.
Cell Mol Immunol ; 9(3): 197-207, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22522654

RESUMO

In this review, we summarize the major fundamental advances in immunological research reported in 2011. The highlights focus on the improved understanding of key questions in basic immunology, including the initiation and activation of innate responses as well as mechanisms for the development and function of various T-cell subsets. The research includes the identification of novel cytosolic RNA and DNA sensors as well as the identification of the novel regulators of the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Moreover, remarkable advances have been made in the developmental and functional properties of innate lymphoid cells (ILCs). Helper T cells and regulatory T (Treg) cells play indispensable roles in orchestrating adaptive immunity. There have been exciting discoveries regarding the regulatory mechanisms of the development of distinct T-cell subsets, particularly Th17 cells and Treg cells. The emerging roles of microRNAs (miRNAs) in T cell immunity are discussed, as is the recent identification of a novel T-cell subset referred to as follicular regulatory T (TFR) cells.


Assuntos
Alergia e Imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Receptores Toll-Like/imunologia , Imunidade Adaptativa/genética , Alergia e Imunologia/tendências , Animais , Humanos , Imunidade Inata/genética , Imunomodulação , Ativação Linfocitária , MicroRNAs/imunologia , Pesquisa , Transdução de Sinais/imunologia
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