Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Adv Exp Med Biol ; 1172: 79-96, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628652

RESUMO

The Interleukin (IL)-10 cytokine family includes IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26, which are considered as Class 2α-helical cytokines. IL-10 is the most important cytokine in suppressing pro-inflammatory responses in all kinds of autoimmune diseases and limiting excessive immune responses. Due to protein structure homology and shared usage of receptor complexes as well as downstream signaling pathway, other IL-10 family cytokines also show indispensable functions in immune regulation, tissue homeostasis, and host defense. In this review, we focus on immune functions and structures of different cytokines in this family and try to better understand how their molecular mechanisms connect to their biological functions. The molecular details regarding their actions also provide useful information in developing candidate immune therapy reagents for a variety of diseases.


Assuntos
Interleucina-10 , Doenças Autoimunes/imunologia , Humanos , Imunoterapia , Interleucina-10/química , Interleucina-10/imunologia , Transdução de Sinais/imunologia , Relação Estrutura-Atividade
2.
Gut ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506328

RESUMO

OBJECTIVE: Macrophage interleukin (IL)-10 signalling plays a critical role in the maintenance of a regulatory phenotype that prevents the development of IBD. We have previously found that anti-tumour necrosis factor (TNF) monoclonal antibodies act through Fcγ-receptor (FcγR) signalling to promote repolarisation of proinflammatory intestinal macrophages to a CD206+ regulatory phenotype. The role of IL-10 in anti-TNF-induced macrophage repolarisation has not been examined. DESIGN: We used human peripheral blood monocytes and mouse bone marrow-derived macrophages to study IL-10 production and CD206+ regulatory macrophage differentiation. To determine whether the efficacy of anti-TNF was dependent on IL-10 signalling in vivo and in which cell type, we used the CD4+CD45Rbhigh T-cell transfer model in combination with several genetic mouse models. RESULTS: Anti-TNF therapy increased macrophage IL-10 production in an FcγR-dependent manner, which caused differentiation of macrophages to a more regulatory CD206+ phenotype in vitro. Pharmacological blockade of IL-10 signalling prevented the induction of these CD206+ regulatory macrophages and diminished the therapeutic efficacy of anti-TNF therapy in the CD4+CD45Rbhigh T-cell transfer model of IBD. Using cell type-specific IL-10 receptor mutant mice, we found that IL-10 signalling in macrophages but not T cells was critical for the induction of CD206+ regulatory macrophages and therapeutic response to anti-TNF. CONCLUSION: The therapeutic efficacy of anti-TNF in resolving intestinal inflammation is critically dependent on IL-10 signalling in macrophages.

3.
J Immunol ; 201(10): 2934-2946, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30315140

RESUMO

IL-6 is a critical driver of acute and chronic inflammation and has been reported to act as a T cell survival factor. The influence of IL-6 on T cell homeostasis is not well resolved. We demonstrate that IL-6 signaling drives T cell expansion under inflammatory conditions but not during normal homeostasis. During inflammation, IL-6Rα-deficient T cells are unable to effectively compete with wild type T cells. IL-6 promotes T cell proliferation, and this is associated with low-level expression of the RORγt transcription factor. T cells upregulate Rorc mRNA at levels substantially diminished from that seen in Th17 cells. Blockade of RORγt through genetic knockout or a small molecule inhibitor leads to T cell expansion defects comparable to those in IL-6Rα-deficient T cells. Our results indicate that IL-6 plays a key role in T cell expansion during inflammation and implicates a role for the transient induction of low-level RORγt.

4.
Sci Rep ; 6: 37543, 2016 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-27869234

RESUMO

Although the TCR repertoire is highly diverse, a small fraction of TCR chains, referred to as public, preferentially form and are shared by most individuals. Prior studies indicated that public TCRß may be preferentially deployed in autoimmunity. We hypothesized that if these TCRß modulate the likelihood of a TCRαß heterodimer productively engaging autoantigen, because they are widely present in the population and often high frequency within individual repertoires, they could also broadly influence repertoire responsiveness to specific autoantigens. We assess this here using a series of public and private TCRß derived from autoimmune encephalomyelitis-associated TCR. Transgenic expression of public, but not private, disease-associated TCRß paired with endogenously rearranged TCRα endowed unprimed T cells with autoantigen reactivity. Further, two of six public, but none of five private TCRß provoked spontaneous early-onset autoimmunity in mice. Our findings indicate that single TCRß are sufficient to confer on TCRαß chains reactivity toward disease-associated autoantigens in the context of diverse TCRα. They further suggest that public TCR can skew autoimmune susceptibility, and that subsets of public TCR sequences may serve as disease- specific biomarkers or therapeutic targets.


Assuntos
Doenças Autoimunes/imunologia , Suscetibilidade a Doenças , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Sequência de Aminoácidos , Animais , Doenças Autoimunes/patologia , Autoimunidade , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Multimerização Proteica , Receptores de Antígenos de Linfócitos T alfa-beta/química , Linfócitos T/imunologia
6.
Sensors (Basel) ; 16(2): 186, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26848662

RESUMO

An empirical tropospheric delay model, together with a mapping function, is commonly used to correct the tropospheric errors in global navigation satellite system (GNSS) processing. As is well-known, the accuracy of tropospheric delay models relies mainly on the correction efficiency for tropospheric wet delays. In this paper, we evaluate the accuracy of three tropospheric delay models, together with five mapping functions in wet delays calculation. The evaluations are conducted by comparing their slant wet delays with those measured by water vapor radiometer based on its satellite-tracking function (collected data with large liquid water path is removed). For all 15 combinations of three tropospheric models and five mapping functions, their accuracies as a function of elevation are statistically analyzed by using nine-day data in two scenarios, with and without meteorological data. The results show that (1) no matter with or without meteorological data, there is no practical difference between mapping functions, i.e., Chao, Ifadis, Vienna Mapping Function 1 (VMF1), Niell Mapping Function (NMF), and MTT Mapping Function (MTT); (2) without meteorological data, the UNB3 is much better than Saastamoinen and Hopfield models, while the Saastamoinen model performed slightly better than the Hopfield model; (3) with meteorological data, the accuracies of all three tropospheric delay models are improved to be comparable, especially for lower elevations. In addition, the kinematic precise point positioning where no parameter is set up for tropospheric delay modification is conducted to further evaluate the performance of tropospheric delay models in positioning accuracy. It is shown that the UNB3 model is best and can achieve about 10 cm accuracy for the N and E coordinate component while 20 cm accuracy for the U coordinate component no matter the meteorological data is available or not. This accuracy can be obtained by the Saastamoinen model only when meteorological data is available, and degraded to 46 cm for the U component if the meteorological data is not available.

7.
J Immunol ; 196(7): 2973-85, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26912317

RESUMO

How a large number of cytokines differentially signal through a small number of signal transduction pathways is not well resolved. This is particularly true for IL-6 and IL-10, which act primarily through STAT3 yet induce dissimilar transcriptional programs leading alternatively to pro- and anti-inflammatory effects. Kinetic differences in signaling, sustained to IL-10 and transient to IL-6, are critical to this in macrophages. T cells are also key targets of IL-6 and IL-10, yet how differential signaling in these cells leads to divergent cellular fates is unclear. We show that, unlike for macrophages, signal duration cannot explain the distinct effects of these cytokines in T cells. Rather, naive, activated, activated-rested, and memory CD4(+) T cells differentially express IL-6 and IL-10 receptors in an activation state-dependent manner, and this impacts downstream cytokine effects. We show a dominant role for STAT3 in IL-6-mediated Th17 subset maturation. IL-10 cannot support Th17 differentiation because of insufficient cytokine receptivity rather than signal quality. Enforced expression of IL-10Rα on naive T cells permits an IL-10-generated STAT3 signal equivalent to that of IL-6 and equally capable of promoting Th17 formation. Similarly, naive T cell IL-10Rα expression also allows IL-10 to mimic the effects of IL-6 on both Th1/Th2 skewing and Tfh cell differentiation. Our results demonstrate a key role for the regulation of receptor expression rather than signal quality or duration in differentiating the functional outcomes of IL-6 and IL-10 signaling, and identify distinct signaling properties of these cytokines in T cells compared with myeloid cells.


Assuntos
Diferenciação Celular , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais , Células Th17/citologia , Células Th17/metabolismo , Animais , Expressão Gênica , Imunofenotipagem , Interleucina-10/farmacologia , Subunidade alfa de Receptor de Interleucina-10/genética , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Interleucina-6/farmacologia , Subunidade alfa de Receptor de Interleucina-6/genética , Subunidade alfa de Receptor de Interleucina-6/metabolismo , Camundongos , Camundongos Transgênicos , Fenótipo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/citologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th2/citologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo
8.
Sensors (Basel) ; 15(12): 29893-909, 2015 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-26633400

RESUMO

With the increased availability of regional reference networks, Precise Point Positioning (PPP) can achieve fast ambiguity resolution (AR) and precise positioning by assimilating the satellite fractional cycle biases (FCBs) and atmospheric corrections derived from these networks. In such processing, the atmospheric corrections are usually treated as deterministic quantities. This is however unrealistic since the estimated atmospheric corrections obtained from the network data are random and furthermore the interpolated corrections diverge from the realistic corrections. This paper is dedicated to the stochastic modelling of atmospheric corrections and analyzing their effects on the PPP AR efficiency. The random errors of the interpolated corrections are processed as two components: one is from the random errors of estimated corrections at reference stations, while the other arises from the atmospheric delay discrepancies between reference stations and users. The interpolated atmospheric corrections are then applied by users as pseudo-observations with the estimated stochastic model. Two data sets are processed to assess the performance of interpolated corrections with the estimated stochastic models. The results show that when the stochastic characteristics of interpolated corrections are properly taken into account, the successful fix rate reaches 93.3% within 5 min for a medium inter-station distance network and 80.6% within 10 min for a long inter-station distance network.

9.
Sci Rep ; 5: 14488, 2015 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-26412089

RESUMO

While the molecular mechanisms promoting activation of the Nod-like Receptor (NLR) family member NLRP3 inflammasome are beginning to be defined, little is known about the mechanisms that regulate the NLRP3 inflammasome. Acute (up to 4 hours) LPS stimulation, followed by ATP is frequently used to activate the NLRP3 inflammasome in macrophages. Interestingly, we observed that the ability of LPS to license NLRP3 is transient, as prolonged (12 to 24 hours) LPS exposure was a relatively ineffective priming stimulus. This suggests that relative to acute LPS, chronic LPS exposure triggers regulatory mechanisms to dampen NLRP3 activation. Transfer of culture supernatants from macrophages stimulated with LPS for 24 hours dramatically reduced ATP- and nigericin-induced NLRP3 inflammasome activation in naïve macrophages. We further identified IL-10 as the secreted inflammasome-tolerizing factor that acts in an autocrine manner to control activation of the NLRP3 inflammasome. Finally, we demonstrated that IL-10 dampens NLRP3 expression to control NLRP3 inflammasome activation and subsequent caspase-8 activation. In conclusion, we have uncovered a mechanism by which chronic, but not acute, LPS exposure induces IL-10 to dampen NLRP3 inflammasome activation to avoid overt inflammation.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Caspase 8/metabolismo , Expressão Gênica , Inflamassomos/metabolismo , Interleucina-10/metabolismo , Receptores Toll-Like/agonistas , Animais , Citocinas/metabolismo , Ativação Enzimática , Regulação da Expressão Gênica , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR
10.
Nat Commun ; 6: 6131, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25607885

RESUMO

Polymorphisms attenuating IL-10 signalling confer genetic risk for inflammatory bowel disease. Yet, how IL-10 prevents mucosal autoinflammation is incompletely understood. We demonstrate using lineage-specific deletions of IL-10Rα that IL-10 acts primarily through macrophages to limit colitis. Colitis depends on IL-6 to support pathologic Th17 cell generation in wild-type mice. However, specific ablation of macrophage IL-10Rα provokes excessive IL-1ß production that overrides Th17 IL-6 dependency, amplifying the colonic Th17 response and disease severity. IL-10 not only inhibits pro-IL-1ß production transcriptionally in macrophages, but suppresses caspase-1 activation and caspase-1-dependent maturation of pro-IL-1ß to IL-1ß. Therefore, lineage-specific effects of IL-10 skew the cytokine dependency of Th17 cell development required for colitis pathogenesis. Coordinated interventions may be needed to fully suppress Th17-mediated immunopathology.


Assuntos
Interleucina-10/metabolismo , Macrófagos/metabolismo , Células Th17/metabolismo , Animais , Caspase 1/metabolismo , Linhagem da Célula , Colite/genética , Colite/metabolismo , Colo/metabolismo , Citocinas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Homeodomínio/genética , Inflamassomos , Inflamação , Doenças Inflamatórias Intestinais/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Risco , Transdução de Sinais , Transgenes
11.
Eur J Immunol ; 43(5): 1195-207, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23436224

RESUMO

The fate of Foxp3(+) regulatory T (Treg) cells responding during autoimmunity is not well defined. We observed a marked elevation in KLRG1(+) (where KLRG1 stands for killer cell lectin-like receptor G1) CNS-infiltrating Treg cells in experimental autoimmune encephalomyelitis (EAE), and assessed their origin and properties. KLRG1(+) Treg cells showed increased activation marker expression, Foxp3 and CD25 levels, and more rapid cell cycling than KLRG1(-) cells. KLRG1(-) Treg cells converted into KLRG1(+) cells and this was increased in autoimmune inflammation. Conversion was unidirectional; KLRG1(+) Treg cells did not revert to a KLRG1(-) state. KLRG1(+) but notKLRG1(-) Treg cells survived poorly, indicative of terminal differentiation. This was associated with diminished BCL2 and increased apoptosis of isolated cells. KLRG1 was also upregulated on iTreg cells after transfer and EAE induction or on iTreg cells developing spontaneously during EAE. KLRG1(+) Treg cells produced more IL-10 and had altered effector cytokine production compared with their KLRG1(-) counterparts. Despite their differences, KLRG1(+) and KLRG1(-) Treg cells proved similarly potent in suppressing EAE. KLRG1(+) and KLRG1(-) populations were phenotypically heterogeneous, with the extent and pattern of activation marker expression dependent both on cellular location and inflammation. Our results support an extensive diversification of Treg cells during EAE, and associate KLRG1 with altered Treg-cell function and senescence.


Assuntos
Senescência Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Fatores de Transcrição Forkhead/imunologia , Receptores Imunológicos/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Apoptose , Autoimunidade , Diferenciação Celular , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Fatores de Transcrição Forkhead/genética , Expressão Gênica , Imunofenotipagem , Interleucina-10/biossíntese , Interleucina-10/imunologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Linfócitos T Reguladores/classificação , Linfócitos T Reguladores/patologia , Linfócitos T Reguladores/transplante , Regulação para Cima
12.
J Immunol ; 181(10): 7221-9, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18981144

RESUMO

Regulatory T cells (Tregs), which are characterized by expression of CD4, CD25, and Foxp3, play a crucial role in the control of immune responses to both self and non-self Ags. To date, there are only limited data on their role in physiological and pathological hepatic immune responses. In this study, we examined the role of hepatic Tregs in immune-mediated liver injury by using the murine Con A-induced hepatitis model. Con A treatment was associated with an increased number of Foxp3(+) Tregs in liver but not in spleen. Moreover, the expression levels of Foxp3, CTLA-4, glucocorticoid-induced TNF receptor, as well as the frequency of CD103 of Tregs were increased after Con A injection, being significantly higher in liver than in spleen. Depleting CD25(+) cells aggravated liver injury, whereas adoptively transferring CD25(+) cells or Tregs reduced liver injury in Con A-treated recipients. Con A treatment induced elevated serum levels and hepatic mononuclear mRNA expressions of TGF-beta, which were reduced by Tregs depletion. In addition, anti-TGF-beta mAbs blocked the suppressive function of Tregs from Con A-treated mice in vitro. Finally, TGF-beta receptor II dominant-negative mice, whose T cells express a dominant negative form of TGFbetaRII and therefore cannot respond to TGF-beta, had a higher mortality rate and severer liver injury than normal mice injected with the same dose of Con A. These results indicate that CD4(+)CD25(+) Tregs play an important role in limiting the liver injury in Con A-induced hepatitis via a TGF-beta-dependent mechanism.


Assuntos
Hepatite/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Antígenos CD/biossíntese , Apoptose/imunologia , Antígeno CTLA-4 , Concanavalina A/toxicidade , Citometria de Fluxo , Fatores de Transcrição Forkhead/biossíntese , Hepatite/metabolismo , Marcação In Situ das Extremidades Cortadas , Cadeias alfa de Integrinas/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Mitógenos/toxicidade , Receptores do Fator de Necrose Tumoral/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/metabolismo
13.
Immunity ; 29(3): 391-403, 2008 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-18703361

RESUMO

The transcriptional control of CD1d-restricted NKT cell development has remained elusive. We report that PLZF (promyelocytic leukemia zinc finger, Zbtb16), a member of the BTB/POZ-ZF family of transcription factors that includes the CD4-lineage-specific c-Krox (Th-POK), is exquisitely specific to CD1d-restricted NKT cells and human MR1-specific MAIT cells. PLZF was induced immediately after positive selection of NKT cell precursors, and PLZF-deficient NKT cells failed to undergo the intrathymic expansion and effector differentiation that characterize their lineage. Instead, they preserved a naive phenotype and were directed to lymph nodes. Conversely, transgenic expression of PLZF induced CD4(+) thymocytes to acquire effector differentiation and migrate to nonlymphoid tissues. We suggest that PLZF is a transcriptional signature of NKT cells that directs their innate-like effector differentiation during thymic development.


Assuntos
Fatores de Transcrição Kruppel-Like/metabolismo , Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Linhagem da Célula , Humanos , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Proteína com Dedos de Zinco da Leucemia Promielocítica , Baço/citologia , Baço/imunologia , Linfócitos T/citologia , Linfócitos T/metabolismo , Timo/citologia , Timo/imunologia
14.
Hepatology ; 43(6): 1211-9, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16729307

RESUMO

Administration of concanavalin A (Con A) induces a rapid and severe liver injury in mice. Natural killer T (NKT) cells are recognized to be the key effector cells, and a variety of cytokines [e.g., interleukin 4 (IL-4), IL-5, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha)] have been shown to play vital roles in Con A-induced liver injury, whereas the role of IL-15, a critical cytokine in the development and homeostasis of NKT cells, remains obscure. In this study, pretreatment with IL-15 prevented mice from Con A-induced mortality, elevation of serum transaminase, liver necrosis, and hepatocyte apoptosis. Depletion of NKT cells abolished Con A-induced liver injury, which could be restored by adoptive transfer of purified NKT cells but not by that of in vivo or in vitro IL-15-treated hepatic NKT cells. Furthermore, transfer of wild-type NKT cells to CD1d-/- mice restored liver injury, whereas transfer of IL-15-treated NKT cells did not. IL-15 pretreatment decreased the NKT-derived IL-4, IL-5, and TNF-alpha production, thereby resulting in less infiltration of eosinophils, which play a critical role in Con A-induced liver injury. In conclusion, IL-15 protects against Con A-induced liver injury via an NKT cell-dependent mechanism by reducing their production of IL-4, IL-5, and infiltration of eosinophils. These findings suggest that IL-15 may be of therapeutic relevance in human autoimmune-related hepatitis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Mediadores da Inflamação/metabolismo , Interleucina-15/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Animais , Biópsia por Agulha , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Concanavalina A , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Mediadores da Inflamação/análise , Células Matadoras Naturais/citologia , Testes de Função Hepática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Probabilidade , Valores de Referência , Sensibilidade e Especificidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA