RESUMO
Hybrid metal halide materials with charming phase transition behaviors have attracted considerable attention. In former works, much attention has been focused on the phase transition triggered by the order-disorder or displacement motions of the organic component. However, manipulating the variation of the inorganic component to achieve the phase transition has rarely been reported. Herein, two novel organic-inorganic hybrid materials, [THPM]n[AgX2]n (THPM = 3,4,5,6-tetrahydropyrimidin-1-ium, X = I for 1 and Br for 2) with the [AgX2]nn- anionic chain structure, were synthesized. At 293 K, the [AgX2]nn- chains in 1 were constructed by the tetramer units of Ag atoms, while that in 2 was assembled by the dimer structure. Upon heating to 355 K, owing to the variation of the metallophilic interaction between adjacent Ag atoms, a unique transformation process from tetramer to dimer in [AgI2]nn- chains of 1 can be detected and endow 1 with a giant anisotropic thermal expansion with linear strain of â¼7% and shear strain of â¼20%, which can be used as a mechanical actuator for switching. Alternatively, for 2, no phase transition process can be observed upon the temperature variation. This work provides an effective approach to design phase transition materials triggered by the inorganic part.
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Diabetes is a major metabolic disease and health issue worldwide that imposes a heavy burden. Research on its pathogenesis and development of effective treatments are currently our major national demands. With the advent of organoid technology, islet organoids have emerged and are attracting increasing attention as a promising model for diabetes research. The establishment of islet organoids is based on the current understanding of islet development. With addition of extra induction factors in vitro to programmatically activate or inhibit specific signaling pathways during islet development, stem cells can be induced to differentiate into three-dimensional cell cultures that possess structures and functions similar to those of natural islets. Because of their capability to mimic the development of islets in vitro, faithfully replicate islet structure, and perform islet physiological functions, islet organoids have been widely used as a valuable tool for the investigation of diabetes pathogenesis, drug screening and evaluation, and clinical transplantation, showing a great potential application. This paper reviews the current research progress, application, and challenges of islet organoids, and discusses the future directions for research on islet organoids.
Assuntos
Diabetes Mellitus , Organoides , Humanos , Células-Tronco , TecnologiaRESUMO
Critical roles of IL-27 in autoimmune diseases and infections have been reported; however, the contribution of endogenous IL-27 to tumor progression remains elusive. In this study, by using IL-27p28 conditional knockout mice, we demonstrate that IL-27 is critical in protective immune response against methyl-cholanthrene-induced fibrosarcoma and transplanted B16 melanoma, and dendritic cells (DCs) are the primary source. DC-derived IL-27 is required for shaping tumor microenvironment by inducing CXCL-10 expression in myeloid-derived suppressor cells and regulating IL-12 production from DCs, which lead to the recruitment and activation of NK and NKT cells resulting in immunological control of tumors. Indeed, reconstitution of IL-27 or CXCL-10 in tumor site significantly inhibits tumor growth and restores the number and activation of NK and NKT cells. In summary, our study identifies a previous unknown critical role of DC-derived IL-27 in NK and NKT cell-dependent antitumor immunity through shaping tumor microenvironment, and sheds light on developing novel therapeutic approaches based on IL-27.
Assuntos
Células Dendríticas/imunologia , Interleucinas/fisiologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/prevenção & controle , Células T Matadoras Naturais/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Células Dendríticas/metabolismo , Tolerância Imunológica , Células Matadoras Naturais/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/metabolismoRESUMO
UNLABELLED: Interleukin (IL)-27, a newly discovered IL-12 family cytokine, is composed of p28 and EBI3. In this study, CD11c-p28(f/f) conditional knockout mice were generated to delete p28 specifically in dendritic cells (DCs). We demonstrated that in the absence of DC-derived p28, these mice were highly susceptible to both low and higher concentrations of concanavalin A (ConA) (5 mg/kg or 10 mg/kg), with extremely early and steady high levels of interferon-γ (IFN-γ) in sera. Neutralizing IFN-γ prevented ConA-induced liver damage in these mice, indicating a critical role of IFN-γ in this pathological process. Interestingly, the main source of the increased IFN-γ in CD11c-p28(f/f) mice was CD4+ T cells, but not natural killer T (NKT) cells. Depletion of CD4+ , but not NK1.1+ , cells completely abolished liver damage, whereas transferring CD4+ T cells from CD11c-p28(f/f) mice, but not from wild-type mice or CD11c-p28(f/f) -IFN-γ(-/-) double knockout mice to CD4(-/-) mice, restored the increased liver damage. Further studies defined higher levels of IFN-γ and T-bet messenger RNA in naïve CD4+ T cells from CD11c-p28(f/f) mice, and these CD4+ T cells were highly responsive to both low and higher concentrations of anti-CD3, indicating a programmed functional alternation of CD4+ T cells. CONCLUSION: We provide a unique model for studying the pathology of CD4+ T cell-mediated liver injury and reveal a novel function of DC-derived p28 on ConA-induced fulminant hepatitis through regulation of the intrinsic ability for IFN-γ production by CD4+ T cells.
Assuntos
Linfócitos T CD4-Positivos/patologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Concanavalina A/efeitos adversos , Suscetibilidade a Doenças/patologia , Interferon gama/fisiologia , Animais , Antígeno CD11c/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Interferon gama/genética , Interleucina-17/genética , Interleucina-17/fisiologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Masculino , Camundongos , Camundongos KnockoutRESUMO
BACKGROUND: γδ T cells comprise a small subset of T cells and play a protective role against cancer and viral infections; however, their precise role in patients with chronic hepatitis B remains unclear. METHODS: Flow cytometry and immunofunctional assays were performed to analyze the impact of Vδ2 γδ (Vδ2) T cells in 64 immune-activated patients, 22 immune-tolerant carriers, and 30 healthy controls. RESULTS: The frequencies of peripheral and hepatic Vδ2 T cells decreased with disease progression from immune tolerant to immune activated. In the latter group of patients, the decreases in peripheral and intrahepatic frequencies of Vδ2 T cells reversely correlated with alanine aminotransferase levels and histological activity index. These activated terminally differentiated memory phenotypic Vδ2 T cells exhibited impaired abilities in proliferation and chemotaxis, while maintained a relative intact interferon (IFN) γ production. Importantly, Vδ2 T cells, in vitro, significantly suppressed the production of cytokines associated with interleukin 17-producing CD4+ T (Th17) cells through both cell contact-dependent and IFN-γ-dependent mechanisms. CONCLUSIONS: Inflammatory microenvironment in IA patients result in decreased numbers of Vδ2 T cells, which play a novel role by regulating the pathogenic Th17 response to protect the liver in patients with chronic hepatitis B.
Assuntos
Hepatite B Crônica/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologia , Adolescente , Adulto , Processos de Crescimento Celular/imunologia , Quimiotaxia de Leucócito , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estatísticas não ParamétricasRESUMO
OBJECTIVE: To analyze the effects of a novel compound, NK-007, on the prevention and treatment of collagen-induced arthritis (CIA) and the underlying mechanisms. METHODS: We determined the effect of NK-007 on lipopolysaccharide (LPS)-triggered tumor necrosis factor α (TNFα) production by murine splenocytes and a macrophage cell line (RAW 264.7) by enzyme-linked immunosorbent assay, intracellular cytokine staining, and Western blotting. The LPS-boosted CIA model was adopted, and NK-007 or vehicle was administered at different time points after immunization. Mice were monitored for clinical severity of arthritis, and joint tissues were used for histologic examination, cytokine detection, and immunohistochemical staining. Finally, stability of TNFα production and Th17 cell differentiation were studied using quantitative polymerase chain reaction and flow cytometry. RESULTS: NK-007 significantly suppressed LPS-induced TNFα production in vitro. Administration of NK-007 completely blocked CIA development and delayed its progression. Furthermore, treatment with NK-007 at the onset of arthritis significantly inhibited the progress of joint inflammation. Administration of NK-007 also suppressed production of TNFα, interleukin-6 (IL-6), and IL-17A in the joint and reduced percentages of IL-17+ cells among CD4+ and γ/δ T cells in draining lymph nodes. We further demonstrated that NK-007 acted on the stability of TNFα messenger RNA and reduced Th17 cell differentiation. In addition, it significantly inhibited levels of IL-6 and IL-17A in human coculture assay. CONCLUSION: For its effects on the development and progression of CIA and for its therapeutic effect on CIA, NK-007 has great potential to be a therapeutic agent for human rheumatoid arthritis.
Assuntos
Artrite Experimental/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Indolizinas/uso terapêutico , Fenantrenos/uso terapêutico , Células Th17/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Diferenciação Celular/imunologia , Linhagem Celular , Indolizinas/farmacologia , Interleucina-17/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Fenantrenos/farmacologia , Estabilidade de RNA/efeitos dos fármacos , Estabilidade de RNA/imunologia , Células Th17/imunologia , Células Th17/metabolismoRESUMO
It has been demonstrated that the two main subsets of peripheral γδ T cells, Vγ1 and Vγ4, have divergent functions in many diseases models. Recently, we reported that Vγ4 γδ T cells played a protective role in tumor immunity through eomesodermin-controlled mechanisms. However, the precise roles of Vγ1 γδ T cells in tumor immunity, especially whether Vγ1 γδ T cells have any interaction with Vγ4 γδ T cells, remain unknown. We demonstrated in this paper that Vγ1 γδ T cells suppressed Vγ4 γδ T cell-mediated antitumor function both in vitro and in vivo, and this suppression was cell contact independent. Using neutralizing anti-IL-4 Ab or IL-4(-/-) mice, we determined the suppressive factor derived from Vγ1 γδ T cells was IL-4. Indeed, treatment of Vγ4 γδ T cells with rIL-4 significantly reduced expression levels of NKG2D, perforin, and IFN-γ. Finally, Vγ1 γδ T cells produced more IL-4 and expressed significantly higher level of GATA-3 upon Th2 priming in comparison with Vγ4 γδ T cells. Therefore, to our knowledge, our results established for the first time a negative regulatory role of Vγ1 γδ T cells in Vγ4 γδ T cell-mediated antitumor immunity through cell contact-independent and IL-4-mediated mechanisms. Selective depletion of this suppressive subset of γδ T cells may be beneficial for tumor immune therapy.
Assuntos
Regulação para Baixo/imunologia , Interleucina-4/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/biossíntese , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Animais , Comunicação Celular/genética , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Regulação para Baixo/genética , Interleucina-4/deficiência , Interleucina-4/genética , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/prevenção & controle , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T gama-delta/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T gama-delta/genética , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Microambiente Tumoral/genéticaRESUMO
Con A-induced fulminant hepatitis is a well-known animal model for acute liver failure. However, the role of γδ T cells in this model is undefined. In this report, using TCR δ(-/-) mice, we demonstrated a protective role of γδ T cells in Con A-induced hepatitis model. TCR δ(-/-) mice showed significantly decreased levels of IL-17A and IL-17F in the Con A-treated liver tissue, and reconstitution of TCR δ(-/-) mice with wild-type (Wt), but not IL-17A(-/-), γδ T cells significantly reduced hepatitis, strongly suggesting a critical role of IL-17A in mediating the protective effect of γδ T cells. Interestingly, only Vγ4, but not Vγ1, γδ T cells exerted such a protective effect. Furthermore, depletion of NKT cells in TCR δ(-/-) mice completely abolished hepatitis, and NKT cells from Con A-challenged liver tissues of TCR δ(-/-) mice expressed significantly higher amounts of proinflammatory cytokine IFN-γ than those from Wt mice, indicating that γδ T cells protected hepatitis through targeting NKT cells. Finally, abnormal capacity of IFN-γ production by NKT cells of TCR δ(-/-) mice could only be downregulated by transferring Wt, but not IL-17(-/-), Vγ4 γδ T cells, confirming an essential role of Vγ4-derived IL-17A in regulating the function of NKT cells. In summary, our report thus demonstrated a novel function of Vγ4 γδ T cells in mediating a protective effect against Con A-induced fulminant hepatitis through negatively regulating function of NKT cells in an IL-17A-dependent manner, and transferring Vγ4 γδ T cells may provide a novel therapeutic approach for this devastating liver disease.
Assuntos
Concanavalina A/toxicidade , Regulação para Baixo/imunologia , Interleucina-17/fisiologia , Falência Hepática Aguda/imunologia , Falência Hepática Aguda/prevenção & controle , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/biossíntese , Subpopulações de Linfócitos T/imunologia , Animais , Concanavalina A/antagonistas & inibidores , Modelos Animais de Doenças , Regulação para Baixo/genética , Feminino , Interferon gama/antagonistas & inibidores , Interferon gama/biossíntese , Interleucina-17/deficiência , Interleucina-17/genética , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/patologia , Receptores de Antígenos de Linfócitos T gama-delta/classificação , Receptores de Antígenos de Linfócitos T gama-delta/deficiência , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/fisiologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologiaRESUMO
Although many cancer vaccines have been developed against type I MAGE (melanoma antigen) genes owing to their shared tumour-specific expression properties, studies about their expression and functions are relatively limited. In the present study, we first identify a non-testis-specific type I MAGE gene, Mageb18 (melanoma antigen family B 18). Mouse Mageb18 is also expressed in digestion- and immune-related tissues as well as testis, and its expression in testis is age-dependent. Mageb18 is expressed in many mouse-derived cell lines, and DNA demethylation and histone acetylation mediate the reactivation of Mageb18 in Mageb18-negtive H22 and C6 cells. We also show that mouse Mageb18 encodes a 46 kDa protein which is predominantly localized in the cytoplasm. In testis, the endogenous MAGEB18 protein is mainly expressed in proliferative spermatogonia and primary and secondary spermatocytes, but less so in spermatids. Finally, we demonstrate that knockdown of MAGEB18 inhibits the growth of B16-F0 cells and induces apoptosis, which correlates with increased levels of TP53 (tumour protein 53), p21, Bax and caspase 3. The results of the present study thus uncover an important phenomenon that the expression of certain type I MAGE genes, at least for Mageb18, is non-testis-specific. Although they can regulate various malignant phenotypes of cancer cells, it is necessary to study further their expression pattern in normal tissues before using them to develop more effective and safer cancer vaccines.
Assuntos
Antígenos de Neoplasias/genética , Apoptose/genética , Proliferação de Células , Melanoma Experimental/patologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Western Blotting , DNA , Metilação de DNA , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
We previously demonstrated that gammadelta T cells played an important role in tumor immune surveillance by providing an early source of IFN-gamma. The precise role of different subsets of gammadelta T cells in the antitumor immune response, however, is unknown. Vgamma1 and Vgamma4 gammadelta T cells are the principal subsets of peripheral lymphoid gammadelta T cells and they might play distinct roles in tumor immunity. In support of this, we observed that reconstitution of TCRdelta(-/-) mice with Vgamma4, but not Vgamma1, gammadelta T cells restored the antitumor response. We also found that these effects were exerted by the activated (CD44(high)) portion of Vgamma4 gammadelta T cells. We further determined that IFN-gamma and perforin are critical elements in the Vgamma4-mediated antitumor immune response. Indeed, CD44(high) Vgamma4 gammadelta T cells produced significantly more IFN-gamma and perforin on activation, and showed greater cytolytic activity than did CD44(high) Vgamma1 gammadelta T cells, apparently due to the high level of eomesodermin (Eomes) in these activated Vgamma4 gammadelta T cells. Consistently, transfection of dominant-negative Eomes in Vgamma4 gammadelta T cells diminished the level of IFN-gamma secretion, indicating a critical role of Eomes in the effector function of these gammadelta T cells. Our results thus reveal distinct functions of Vgamma4 and Vgamma1 gammadelta T cells in antitumor immune response, and identify a protective role of activated Vgamma4 gammadelta T cells, with possible implications for tumor immune therapy.
Assuntos
Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/fisiologia , Proteínas com Domínio T/biossíntese , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Regulação para Cima/imunologia , Animais , Linhagem Celular , Linhagem Celular Tumoral , Técnicas de Cocultura , Citotoxicidade Imunológica , Receptores de Hialuronatos/biossíntese , Receptores de Hialuronatos/fisiologia , Interferon gama/biossíntese , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Perforina/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Proteínas com Domínio T/genéticaRESUMO
The tumor suppressor lethal giant larvae (Lgl) plays a critical role in epithelial cell polarization. However, the molecular mechanism by which Lgl carries out its functions is unclear. In this study, we report that the yeast Lgl proteins Sro7p and Sro77p directly interact with Exo84p, which is a component of the exocyst complex that is essential for targeting vesicles to specific sites of the plasma membrane for exocytosis, and that this interaction is important for post-Golgi secretion. Genetic analyses demonstrate a molecular pathway from Rab and Rho GTPases through the exocyst and Lgl to SNAREs, which mediate membrane fusion. We also found that overexpression of Lgl and t-SNARE proteins not only improves exocytosis but also rescues polarity defects in exocyst mutants. We propose that, although Lgl is broadly distributed in the cells, its localized interaction with the exocyst and kinetic activation are important for the establishment and reenforcement of cell polarity.
Assuntos
Proteínas de Transporte/metabolismo , Exocitose , Proteínas de Membrana/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte/genética , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Polaridade Celular , Fusão de Membrana , Proteínas de Membrana/genética , Microscopia Eletrônica de Transmissão , Mutação , Ligação Proteica , Proteínas SNARE , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/ultraestrutura , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/fisiologia , Transdução de Sinais , Proteínas de Transporte Vesicular/biossíntese , Proteínas rab de Ligação ao GTP/fisiologia , Proteínas rho de Ligação ao GTP/fisiologiaRESUMO
We have previously demonstrated that DCB-3503, a tylophorine analogue, has an anti-inflammatory property in murine models for autoimmune diseases. However, its mechanism remains unknown. Here, we have synthesized 34 derivatives of DCB-3503 and investigated their effects on T cells differentiation and TNF-α production. Six derivatives (4, 9, 13, 19, 31, and 32) could significantly promote the expression of Foxp3. Among these, the IC50 of 31 and 32 was about 500 µM. Eight analogues (1, 2, 4, 9, 12, 18, 19, and 21) showed anti-TNF-α effect in Raw 264.7 cells and murine splenocytes, of which 18 and 19 were most significant. Moreover, 31 and 18 showed a better activity and cell survival ratio when compared with DCB-3503 at various concentrations. In summary, we have demonstrated the anti-inflammatory characteristics of 34 novel tylophorine derivatives and discussed their structure-activity relationship in order to explore their therapeutic potentials for inflammatory diseases.
RESUMO
Our aim is to reveal the role of interleukin 6 (IL-6) in the pathogenesis of systemic lupus erythematosus (SLE) in a murine model of SLE. Normal female C57BL/6 mice were immunized with syngeneic-activated lymphocyte-derived DNA (ALD-DNA) to induce SLE. Non-immunized mice were used as control. SLE-associated markers, including anti-double-stranded DNA (anti-dsDNA) Abs, urine protein, and kidney histopathology, were assayed to ensure the induction of the disease. Compared with control mice, ALD-DNA immunized mice exhibited high levels of anti-dsDNA Abs, IL-6 expression in vivo and in vitro. We also found that IL-6 knockout (IL-6KO) mice were resistant to ALD-DNA-induced SLE. The activation of CD4(+) T cells in immunized IL-6KO mice was lower than in immunized wild-type (Wt) mice. Intracellular cytokine staining showed that Foxp3 expression in immunized IL-6KO mice was higher than in immunized Wt mice, which might be associated with the disease severity. We further discovered that ALD-DNA-stimulated dendritic cells supernatants could result in higher IL-6 and TNF-α expression and could suppress Foxp3 expression. In addition, blocking IL-6 could up-regulate Foxp3 expression. Therefore, our findings show that IL-6 promotes the progression of SLE via suppressing Treg differentiation.
Assuntos
Anticorpos Antinucleares/imunologia , Interleucina-6/metabolismo , Rim/patologia , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Reguladores/imunologia , Animais , DNA/imunologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Tregs (Foxp3+CD4+) are enriched in tumors to foster a tolerant microenvironment that inhibits antitumor immune response. IL-27 is reported to regulate the development and function of Tregs in vitro and in vivo; however, the effects of endogenous IL-27 on Tregs in the tumor microenvironment remain elusive. We demonstrated that in the absence of DC-derived IL-27, Tregs were decreased significantly in transplanted B16 melanoma, transplanted EL-4 lymphoma, and MCA-induced fibrosarcoma by using IL-27p28 conditional KO mice. Further studies revealed that IL-27 promoted the expression of CCL22, which is established to mediate the recruitment of peripheral Tregs into tumors. Tumor-associated DCs were identified as the major source of CCL22 in tumor sites, and IL-27 could induce CCL22 expression in an IL-27R-dependent manner. Intratumoral reconstitution of rmCCL22 or rmIL-27, but not rmIL-27p28, significantly restored the tumor infiltration of Tregs in IL-27p28 KO mice. Correlated with a decreased number of Tregs, tumor-infiltrating CD4 T cells were found to produce much more IFN-γ in IL-27p28 KO mice, which highlighted the physiological importance of Tregs in suppressing an antitumor immune response. Overall, our results identified a novel mechanism of action of IL-27 on Tregs in the context of cancers.
Assuntos
Movimento Celular/imunologia , Células Dendríticas/imunologia , Interleucinas/imunologia , Linfoma/imunologia , Melanoma/imunologia , Proteínas de Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Movimento Celular/genética , Quimiocina CCL22/genética , Quimiocina CCL22/imunologia , Células Dendríticas/patologia , Regulação Neoplásica da Expressão Gênica/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucinas/genética , Linfoma/genética , Linfoma/patologia , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Linfócitos T Reguladores/patologiaRESUMO
CD8(+) T cells play an important role in immune regulation and effective immune responses against tumor cells, viral infection, and intracellular pathogens. In this report, using tiger or 10BiT mice, we defined a population of IL-10-producing CD8(+) T cells that were induced by IL-4. These IL-10(+)CD8(+) T cells possessed a strong inhibitory effect on the CD4(+) T cell proliferation in an IL-10-dependent and cell contact-dependent fashion. In comparison with IL-10(-)CD8(+) T cells, IL-10(+)CD8(+) T cells expressed an array of Th2-like cytokines (IL-4, IL-5), perforin, and granzymes, as well as the cell cycle regulatory protein Cdkn2a. Interestingly, knockdown of cdkn2a using siRNA reduced IL-4-induced IL-10 production significantly. Furthermore, CD8(+) T cells from Cdkn2a(-/-) mice produced a significantly lower amount of IL-10, and the effect was limited to CD8(+) T cells but not observed in CD4(+) T cells and APCs. Finally, IL-10(+)CD8(+) T cells played a protective role in the TNBS-induced murine colitis model, indicating a critical role of this population of CD8(+) T cells in regulatory immune responses. Taken together, we have defined a population of IL-10-producing CD8(+) Tregs induced by IL-4 and mediated by Cdkn2a.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Interleucina-10/imunologia , Interleucina-4/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Modelos Animais de Doenças , Interleucina-10/genética , Interleucina-4/genética , Interleucina-5/genética , Interleucina-5/imunologia , Camundongos , Camundongos Knockout , Células Th2/imunologiaRESUMO
Asthmatic inflammation is mediated by a type 2 helper T cell (Th2) cytokine response, and blocking Th2 cytokine production is proven to have a potent therapeutic effect against asthmatic inflammation. Using IL-4-green fluorescent protein (GFP) reporter mice, we demonstrated that Bavachinin, a single compound isolated from a Chinese herb, significantly inhibited Th2 cytokine production, including IL-4, IL-5 and IL-13. Notably, this compound almost completely blocked inflammation in the ovalbumin (OVA)-sensitized animal asthma model. Furthermore, we demonstrated that this chemical selectively affects the level of GATA-3, most likely by affecting the stability of GATA-3 mRNA. Our results demonstrate, for the first time, the potential therapeutic value of this single compound derived from Chinese herbs.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Flavonoides/isolamento & purificação , Flavonoides/uso terapêutico , Hipersensibilidade/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Asma/complicações , Asma/tratamento farmacológico , Asma/imunologia , Asma/fisiopatologia , Hiper-Reatividade Brônquica/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Flavonoides/farmacologia , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Hipersensibilidade/complicações , Hipersensibilidade/imunologia , Inflamação/complicações , Inflamação/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Th2/citologia , Células Th2/efeitos dos fármacos , Células Th2/imunologiaRESUMO
The current study evaluated the glycoproteomic profile of tissues from colon cancer patients. The lectin microarray was first performed to compare the glycoprotein profiles between colon cancer and matched normal tissues. Level of N-acetylglucosamine (GlcNAc) that Solanum tuberosum lectin (STL) bound was found to be elevated in colon cancer, which was verified through lectin histochemistry. The subsequent glycoproteomic analysis based on STL enrichment of glycoproteins followed by label-free quantitative nano liquid chromatography-mass spectrometry/mass spectrometry (nanoLC-MS/MS) analysis identified 72 proteins in high confidence. Among these proteins, 17 were exclusively detected in cancer tissues, and 14 were significantly upregulated in tumor tissues. Annexin A1 and HSP90ß were chosen for further investigation by immunoprecipitation coupled with lectin blots, western blots and tissue microarrays. Both Annexin A1 and HSP90ß were GlcNAcylated, and their protein expressions were elevated in colon cancer, compared to normal tissues. Moreover, specific changes of GlcNAc abundances in Annexin A1 and HSP90ß suggested that tumor-specific glycan patterns could serve as candidate biomarkers of colon cancer for distinguishing cancer patients from healthy individuals.
Assuntos
Neoplasias do Colo/metabolismo , Glicoproteínas/química , Proteoma/química , Proteômica , Idoso , Idoso de 80 Anos ou mais , Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Glicoproteínas/análise , Humanos , Lectinas/química , Lectinas/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise Serial de Proteínas , Proteoma/análise , Proteômica/métodos , Reprodutibilidade dos Testes , Espectrometria de Massas em TandemRESUMO
Tylophorine and analogs are phenanthroindolizidine alkaloids, several of which have been reported to have anticancer, antiviral, and anti-inflammatory properties. However, their function in the immune system remains widely unknown. Transcription factor Foxp3 is critical for the development and function of Treg, which down-regulates the immune system and maintains tolerance to self-antigens. In the present study, we defined a novel tylophorine analog, W-8, enhanced TGF-ß-induced Foxp3 expression at the mRNA and the protein levels. Interestingly, W-8 synergistically increased the level of TGF-ß-induced p-Smad3 through inhibition of the AKT/mTOR pathway and enhanced the demethylation of the promoter region of the Foxp3 through inhibition of the ERK pathway and DNMT1 expression. Moreover, administration of W-8 suppressed TNBS-induced murine colitis and increased Tregs in lymphoid tissues. Finally, W-8 enhanced conversion of naïve T cells to Tregs in vivo. In summary, our results defined a novel compound that enhanced Foxp3 expression through transcriptional and epigenetic programs, and it might serve as a therapeutic agent for inflammatory diseases.