Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Int Immunopharmacol ; 73: 312-320, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31129418

RESUMO

Progressive lung injury and pulmonary inflammation can be induced by an intraperitoneal injection of lipopolysaccharide (LPS). Interleukin-1ß (IL-1ß) is a key pro-inflammatory cytokine that can further exaggerate inflammation, which is cleaved and activated by the NALP3 inflammasome. Although the nuclear receptor Rev-erbα attenuates the level of LPS-induced pulmonary inflammation, the mechanism remains unclear. In this study, we investigated the influence of LPS-induced production of IL-1ß and Rev-erbα on the development of lung inflammation. Herein, we demonstrate that Rev-erbα reduces IL-1ß production and lung injury following an intraperitoneal injection of LPS, which is dependent on the NF-κB/NALP3 pathway. Thus, Rev-erbα is able to decrease the extent of acute lung injury by regulating IL-1ß production. This mechanism may represent a potential novel therapeutic approach for lung injury.


Assuntos
Lesão Pulmonar Aguda/imunologia , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Animais , Glicina/análogos & derivados , Glicina/farmacologia , Interleucina-1beta/imunologia , Isoquinolinas/farmacologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Células RAW 264.7 , Transdução de Sinais , Tiofenos/farmacologia
2.
Nat Commun ; 10(1): 377, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670689

RESUMO

The circadian clock regulates immune responses to microbes and affects pathogen replication, but the underlying molecular mechanisms are not well understood. Here we demonstrate that the circadian components BMAL1 and REV-ERBα influence several steps in the hepatitis C virus (HCV) life cycle, including particle entry into hepatocytes and RNA genome replication. Genetic knock out of Bmal1 and over-expression or activation of REV-ERB with synthetic agonists inhibits the replication of HCV and the related flaviruses dengue and Zika via perturbation of lipid signaling pathways. This study highlights a role for the circadian clock component REV-ERBα in regulating flavivirus replication.


Assuntos
Fatores de Transcrição ARNTL/genética , Relógios Circadianos/genética , Flavivirus/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Replicação Viral/efeitos dos fármacos , Fatores de Transcrição ARNTL/imunologia , Fatores de Transcrição ARNTL/farmacologia , Linhagem Celular , Relógios Circadianos/imunologia , Replicação do DNA , Dengue , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/genética , Flavivirus/efeitos dos fármacos , Flavivirus/metabolismo , Flavivirus/patogenicidade , Regulação da Expressão Gênica/genética , Genes Essenciais/genética , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatite C , Hepatócitos/imunologia , Hepatócitos/virologia , Humanos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/farmacologia , Proteômica , RNA Mensageiro/metabolismo , Internalização do Vírus/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Zika virus/genética , Infecção por Zika virus
3.
J Clin Invest ; 128(6): 2281-2296, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29533925

RESUMO

Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBß in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBα plays the dominant role, as deletion of REV-ERBß alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.


Assuntos
Relógios Circadianos/imunologia , Ritmo Circadiano/imunologia , Homeostase/imunologia , Imunidade Inata , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia , Pneumonia/imunologia , Animais , Relógios Circadianos/genética , Ritmo Circadiano/genética , Homeostase/genética , Camundongos , Camundongos Transgênicos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Pneumonia/genética , Pneumonia/patologia , Proteólise , Sumoilação/genética , Sumoilação/imunologia
4.
Biochem Biophys Res Commun ; 469(2): 151-7, 2016 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-26616049

RESUMO

Under physiological conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic molecules such as cytokines and chemokines, amplifying the initial molecular-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBß (REV-ERBs) are crucial in the regulation of inflammation- and metabolism-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory molecules following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/ml) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms.


Assuntos
Linhagem Celular/imunologia , Citocinas/imunologia , Fatores Imunológicos/imunologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia , Receptores Citoplasmáticos e Nucleares/imunologia , Proteínas Repressoras/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Ratos
5.
Immunity ; 40(2): 178-86, 2014 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-24560196

RESUMO

Immune parameters change with time of day and disruption of circadian rhythms has been linked to inflammatory pathologies. A circadian-clock-controlled immune system might allow an organism to anticipate daily changes in activity and feeding and the associated risk of infection or tissue damage to the host. Responses to bacteria have been shown to vary depending on time of infection, with mice being more at risk of sepsis when challenged ahead of their activity phase. Studies highlight the extent to which the molecular clock, most notably the core clock proteins BMAL1, CLOCK, and REV-ERBα, control fundamental aspects of the immune response. Examples include the BMAL1:CLOCK heterodimer regulating toll-like receptor 9 (TLR9) expression and repressing expression of the inflammatory monocyte chemokine ligand (CCL2) as well as REV-ERBα suppressing the induction of interleukin-6. Understanding the daily rhythm of the immune system could have implications for vaccinations and how we manage infectious and inflammatory diseases.


Assuntos
Ritmo Circadiano/fisiologia , Imunidade , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/fisiologia , Animais , Ritmo Circadiano/genética , Ritmo Circadiano/imunologia , Regulação da Expressão Gênica , Humanos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia
6.
J Biol Chem ; 288(15): 10692-702, 2013 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-23449984

RESUMO

Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erbα is a constitutive transcriptional repressor as it lacks AF2 domain and was earlier shown to be present in macrophages. In the present study, we highlight the differences in the relative subcellular localization of Rev-erbα in monocytes and macrophages. The nuclear localization of Rev-erbα in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erbα elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erbα overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erbα binding site exclusive to humans and higher order primates and not mouse, demonstrating a species barrier in its functionality. This direct gene repression is mediated by recruitment of co-repressors NCoR and HDAC3. In addition, our data elucidate that its overexpression reduced the survival of intracellular pathogen Mycobacterium tuberculosis by enhancing phagosome lysosome maturation, an event resulting from IL10 repression. Thus, these findings suggest that Rev-erbα bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties.


Assuntos
Regulação da Expressão Gênica , Interleucina-10/biossíntese , Macrófagos/metabolismo , Mycobacterium tuberculosis/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Elementos de Resposta , Animais , Linhagem Celular , Feminino , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/patologia , Masculino , Camundongos , Mycobacterium tuberculosis/imunologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia , Especificidade da Espécie , Tuberculose/genética , Tuberculose/imunologia , Tuberculose/metabolismo , Tuberculose/patologia
7.
Proc Natl Acad Sci U S A ; 109(2): 582-7, 2012 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-22184247

RESUMO

Diurnal variation in inflammatory and immune function is evident in the physiology and pathology of humans and animals, but molecular mechanisms and mediating cell types that provide this gating remain unknown. By screening cytokine responses in mice to endotoxin challenge at different times of day, we reveal that the magnitude of response exhibited pronounced temporal dependence, yet only within a subset of proinflammatory cytokines. Disruption of the circadian clockwork in macrophages (primary effector cells of the innate immune system) by conditional targeting of a key clock gene (bmal1) removed all temporal gating of endotoxin-induced cytokine response in cultured cells and in vivo. Loss of circadian gating was coincident with suppressed rev-erbα expression, implicating this nuclear receptor as a potential link between the clock and inflammatory pathways. This finding was confirmed in vivo and in vitro through genetic and pharmacological modulation of REV-ERBα activity. Circadian gating of endotoxin response was lost in rev-erbα(-/-) mice and in cultured macrophages from these animals, despite maintenance of circadian rhythmicity within these cells. Using human macrophages, which show circadian clock gene oscillations and rhythmic endotoxin responses, we demonstrate that administration of a synthetic REV-ERB ligand, or genetic knockdown of rev-erbα expression, is effective at modulating the production and release of the proinflammatory cytokine IL-6. This work demonstrates that the macrophage clockwork provides temporal gating of systemic responses to endotoxin, and identifies REV-ERBα as the key link between the clock and immune function. REV-ERBα may therefore represent a unique therapeutic target in human inflammatory disease.


Assuntos
Ritmo Circadiano/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/imunologia , Interleucina-6/imunologia , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/imunologia , Fatores de Transcrição ARNTL/genética , Análise de Variância , Animais , Endotoxinas/toxicidade , Humanos , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA