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1.
Eur J Immunol ; 48(6): 950-964, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29500823

RESUMO

Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae. Infection of newborn mice with mouse cytomegalovirus (MCMV) intraperitoneally is a well-established model of congenital human cytomegalovirus infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here, we used this model to investigate the role, dynamics, and phenotype of CD8+ T cells in the brain following infection of newborn mice. We show that CD8+ T cells infiltrate the brain and form a pool of tissue-resident memory T cells (TRM cells) that persist for lifetime. Adoptively transferred virus-specific CD8+ T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology, and remain in the brain as TRM cells. Brain CD8+ TRM cells were long-lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8+ TRM cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain.


Assuntos
Encéfalo/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Muromegalovirus/fisiologia , Linfócitos T Citotóxicos/imunologia , Ativação Viral/imunologia , Transferência Adotiva , Animais , Animais Recém-Nascidos , Linfócitos T CD8-Positivos/transplante , Células Cultivadas , Anormalidades Congênitas , Modelos Animais de Doenças , Humanos , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/transplante
2.
Wound Repair Regen ; 25(1): 25-40, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27868279

RESUMO

Dipeptidyl peptidase IV (DPP IV/CD26) is a widely distributed multifunctional protein that plays a significant role in different physiological as well as pathological processes having a broad spectrum of bioactive substrates and immunomodulative properties. It has potential influence on different processes crucial for wound healing, including cell adhesion, migration, apoptosis, and extracellular matrix degradation. However, despite its known enzymatic and immunomodulative functions, limited data characterize the role of DPP IV/CD26 in cutaneous wound healing mechanisms. The aim of this study was to investigate the process of wound healing in conditions of CD26 deficiency in order to obtain better insights on the role of DPP IV/CD26 in cutaneous regeneration. Experimental wounds were made on the dorsal part of CD26 deficient (CD26-/- ) and wild-type mice (C57BL/6). The process of cutaneous wound healing was monitored on defined time schedule postwounding by macroscopic, microscopic, and biochemical analyses. Obtained results revealed a better rate of wound closure, revascularization and cell proliferation in CD26-/- mice, with enhanced local expression of hypoxia-inducible factor 1α and vascular endothelial growth factor. CD26 deficiency induced prompt macrophage recruitment at the site of skin damage but did not influence mobilization of T-cells in comparison with wild-type mice. CD26-/- mice have significantly higher values of IP-10 in serum and control skins compared with wild-type mice but values in wounds did not differ significantly on days 2, 4, and 7 of wound healing. DPP IV/CD26 activity was found to be decreased 4 days postwounding in serum and 2, 4, and 7 days postwounding in wounds of wild-type animals compared with control skins. These findings contribute to better understanding of wound healing mechanisms and could give a support in finding new therapeutic approaches for wound healing and tissue regeneration.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Dipeptidil Peptidase 4/administração & dosagem , Úlcera Cutânea/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Animais , Dipeptidil Peptidase 4/deficiência , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Úlcera Cutânea/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Cicatrização/fisiologia , Ferimentos e Lesões/metabolismo
3.
J Exp Med ; 201(2): 211-20, 2005 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-15642742

RESUMO

The NK cell-activating receptor NKG2D interacts with three different cellular ligands, all of which are regulated by mouse cytomegalovirus (MCMV). We set out to define the viral gene product regulating murine UL16-binding protein-like transcript (MULT)-1, a newly described NKG2D ligand. We show that MCMV infection strongly induces MULT-1 gene expression, but surface expression of this glycoprotein is nevertheless completely abolished by the virus. Screening a panel of MCMV deletion mutants defined the gene m145 as the viral regulator of MULT-1. The MCMV m145-encoded glycoprotein turned out to be necessary and sufficient to regulate MULT-1 by preventing plasma membrane residence of MULT-1. The importance of MULT-1 in NK cell regulation in vivo was confirmed by the attenuating effect of the m145 deletion that was lifted after NK cell depletion. Our findings underline the significance of escaping MULT-1/NKG2D signaling for viral survival and maintenance.


Assuntos
Proteínas de Transporte/metabolismo , Citomegalovirus/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/fisiologia , Proteínas Virais/genética , Animais , Anticorpos Monoclonais/imunologia , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Citomegalovirus/metabolismo , Regulação para Baixo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Ativação Linfocitária/genética , Proteínas de Membrana , Camundongos , Mutação , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Receptores Imunológicos/metabolismo , Receptores de Células Matadoras Naturais , Análise de Sequência de Proteína , Proteínas Virais/metabolismo
4.
Mol Nutr Food Res ; 60(3): 530-41, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26603374

RESUMO

SCOPE: Oleuropein possesses numerous health beneficial effects. We investigated the renoprotective effects of oleuropein against cisplatin (CP) induced kidney injury. METHODS AND RESULTS: Male BALB/cN mice were orally gavaged with 5, 10 and 20 mg oleuropein/kg body weight for 2 days, 48 h after intraperitoneal injection of CP (13 mg/kg). Four days after CP administration, serum creatinine and blood urea nitrogen (BUN) levels were significantly elevated, with histopathological changes in renal tissue. In addition, renal oxidative stress was evidenced by increased expression of 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), cytochrome P450 E1 (CYP2E1) and heme oxygenase-1 (HO-1). The expression of nuclear factor-kappaB (NF-κB) p65, phospho-p65, tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2) in the kidneys increased upon CP treatment, suggesting renal inflammation. CP intoxication increased the expression of p53, Bax and caspase-3 and induced apoptosis in the kidneys. CP administration also resulted in enhanced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). All these effects were dose dependently diminished by oleuropein. Oral administration of PD0325901, an MEK inhibitor, coincided with the oleuropein-mediated suppression of apoptotic, inflammatory and antioxidant markers. CONCLUSION: The results of the current study suggest that oleuropein attenuated CP-induced acute renal injury, which was mediated through the inhibition of ERK signaling.


Assuntos
Injúria Renal Aguda/prevenção & controle , Cisplatino/efeitos adversos , Iridoides/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Administração Oral , Animais , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glucosídeos Iridoides , Iridoides/administração & dosagem , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos Endogâmicos BALB C , Nefrite/induzido quimicamente , Nefrite/tratamento farmacológico , Nefrite/metabolismo , Estresse Oxidativo/efeitos dos fármacos
5.
Food Chem Toxicol ; 62: 397-406, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24025684

RESUMO

The aim of this study was to investigate the therapeutic activity of isoquinoline alkaloid berberine against cisplatin (CP)-induced nephrotoxicity in mice. Berberine was administered at daily doses of 1, 2 and 3 mg/kg by gavage for two successive days, 48 h after intraperitoneal CP injection (13 mg/kg). Mice were sacrificed 24 h after the last dose of berberine. Histopathological changes and the increase in serum creatinine and blood urea nitrogen (BUN) induced by CP were significantly ameliorated by berberine in a dose-dependent manner. Additionally, oxidative/nitrosative stress, evidenced by the increase in renal 4-hydroxynonenal (4-HNE), 3-nitrotyrosine (3-NT), cytochrome P450 E1 (CYP2E1) and heme oxygenase (HO-1) expression, was significantly reduced. The expression of nuclear factor-kappaB (NF-κB), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was markedly suppressed by berberine, indicating the inhibition of inflammatory response. Treatment of CP-intoxicated animals with berberine also significantly reduced the expression of p53, active caspase-3 as well as autophagy marker light chain 3B (LC3B) in the kidneys. The results of the current study showed the nephroprotective activity of berberine against CP-induced renal injury, which could be attributed to the inhibition of oxidative/nitrosative stress, inflammation, autophagy and apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Berberina/farmacologia , Cisplatino/efeitos adversos , Rim/efeitos dos fármacos , Rim/patologia , Nefrite/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Aldeídos/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Citocromo P-450 CYP2E1/metabolismo , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nefrite/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
6.
Food Chem Toxicol ; 51: 370-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23116643

RESUMO

The aim of this study was to investigate the therapeutic potential of rosmarinic acid (RA), a natural phenolic, in the treatment of acute liver toxicity. RA at 10, 25 and 50mg/kg was administered by gavage once daily for 2 consecutive days, 6h after CCl(4) intoxication. CCl(4) intoxication caused hepatic necrosis and increased serum ALT activity. In the livers, oxidative/nitrosative stress was evidenced by increased 3-nitrotyrosine (3-NT) and thiobarbituric acid reactive substances (TBARS) formation and a significant decrease in Cu/Zn superoxide dismutase (SOD) activity. CCl(4) administration triggered inflammatory response in mice livers by activating nuclear factor-kappaB (NF-κB), which coincided with the induction of tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2). RA improved histological and serum markers of liver damage and significantly ameliorated oxidative/nitrosative stress and inflammatory response in liver tissue. Additionally, RA prevented transforming growth factor-beta1 (TGF-ß1) and alpha-smooth muscle actin (α-SMA) expression, suggesting suppression of profibrotic response. Furthermore, RA significantly inhibited the CCl(4)-induced apoptosis, which was evident from decreased cleavage of caspase-3. The hepatoprotective activity of RA coincided with enhanced NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. The results of this study indicates that RA possesses antioxidant, anti-inflammatory, antiapoptotic and antifibrotic activity against acute liver toxicity.


Assuntos
Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Tetracloreto de Carbono/toxicidade , Cinamatos/farmacologia , Depsídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Alanina Transaminase/sangue , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Intoxicação por Tetracloreto de Carbono/metabolismo , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Fígado/metabolismo , Falência Hepática Aguda/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Ácido Rosmarínico
7.
J Clin Invest ; 120(12): 4532-45, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21099111

RESUMO

Human CMV (HCMV) is a major cause of morbidity and mortality in both congenitally infected and immunocompromised individuals. Development of an effective HCMV vaccine would help protect these vulnerable groups. NK group 2, member D (NKG2D) is a potent activating receptor expressed by cells of the innate and adaptive immune systems. Its importance in HCMV immune surveillance is indicated by the elaborative evasion mechanisms evolved by the virus to avoid NKG2D. In order to study this signaling pathway, we engineered a recombinant mouse CMV expressing the high-affinity NKG2D ligand RAE-1γ (RAE-1γMCMV). Expression of RAE-1γ by MCMV resulted in profound virus attenuation in vivo and lower latent viral DNA loads. RAE-1γMCMV infection was efficiently controlled by immunodeficient hosts, including mice lacking type I interferon receptors or immunosuppressed by sublethal γ-irradiation. Features of MCMV infection in neonates were also diminished. Despite tight innate immune control, RAE-1γMCMV infection elicited strong and long-lasting protective immunity. Maternal RAE-1γMCMV immunization protected neonatal mice from MCMV disease via placental transfer of antiviral Abs. Despite strong selective pressure, the RAE-1γ transgene did not exhibit sequence variation following infection. Together, our results indicate that use of a recombinant virus encoding the ligand for an activating NK cell receptor could be a powerful approach to developing a safe and immunogenic HCMV vaccine.


Assuntos
Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Muromegalovirus/genética , Muromegalovirus/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Vacinas Virais/genética , Vacinas Virais/imunologia , Animais , Animais Recém-Nascidos , Sequência de Bases , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Primers do DNA/genética , Feminino , Engenharia Genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/prevenção & controle , Humanos , Imunidade Materno-Adquirida , Células Matadoras Naturais/imunologia , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
8.
J Exp Med ; 205(2): 423-35, 2008 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-18268036

RESUMO

Human cytomegalovirus infection of the developing central nervous system (CNS) is a major cause of neurological damage in newborn infants and children. To investigate the pathogenesis of this human infection, we developed a mouse model of infection in the developing CNS. Intraperitoneal inoculation of newborn animals with murine cytomegalovirus resulted in virus replication in the liver followed by virus spread to the brain. Virus infection of the CNS was associated with the induction of inflammatory responses, including the induction of a large number of interferon-stimulated genes and histological evidence of focal encephalitis with recruitment of mononuclear cells to foci containing virus-infected cells. The morphogenesis of the cerebellum was delayed in infected animals. The defects in cerebellar development in infected animals were generalized and, although correlated temporally with virus replication and CNS inflammation, spatially unrelated to foci of virus-infected cells. Specific defects included decreased granular neuron proliferation and migration, expression of differentiation markers, and activation of neurotrophin receptors. These findings suggested that in the developing CNS, focal virus infection and induction of inflammatory responses in resident and infiltrating mononuclear cells resulted in delayed cerebellar morphogenesis.


Assuntos
Encéfalo/patologia , Doenças do Sistema Nervoso Central/patologia , Infecções por Citomegalovirus/patologia , Animais , Animais Recém-Nascidos , Encéfalo/imunologia , Encéfalo/virologia , Diferenciação Celular , Movimento Celular , Doenças do Sistema Nervoso Central/imunologia , Doenças do Sistema Nervoso Central/virologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Leucócitos Mononucleares/imunologia , Camundongos , Muromegalovirus , Fatores de Crescimento Neural/imunologia , Neuroglia/virologia , Neurônios/citologia , Neurônios/virologia , Receptores Proteína Tirosina Quinases/imunologia
9.
J. physiol. biochem ; 72(3): 405-419, sept. 2016. tab, graf, ilus
Artigo em Inglês | IBECS (Espanha) | ID: ibc-168284

RESUMO

A lot of evidence for the importance of CD26/dipeptidyl peptidase IV (CD26/DPP IV) in immunoactivation has been reported; however, its involvement in colitis remains unclear. The aim of this study was to investigate the influence of CD26/DPP IV deficiency on immunophenotypic changes associated with dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) and CD26-deficient mice. Development of clinical symptoms of colitis and animal health status parameters were assessed; the expression of the nuclear factor (NF)-κB p65 subunit was measured by quantitative real-time PCR, while cell characterization was determined by flow cytometry and immunohistochemical staining. DSS treatment induced loss of body weight and colon length shortening in both mouse strains. An increase of myeloperoxidase activity in CD26-deficient mice was more intensive than in WT mice, in spite of similar histopathological changes. Furthermore, a significant increase in the expression of NF-κB p65 subunit in the colon of CD26-deficient mice was determined. The percentage of splenic CD4+ and CD8+ cells in the acute phase of colitis was significantly decreased in WT mice, while in the same period, an increase in the percentage of splenic CD8+ cells was present in CD26-deficient mice. Development of colitis was accompanied by a significant increase in the percentage of intrahepatic NKT cells in both mouse strains, but their percentage in spleen was increased only in CD26-deficient mice. CD26 deficiency was associated with a heightened response to DSS accompanied by increased expression of NF-κB p65 subunit and distinct changes in leukocyte trafficking. These results provide new insights into the role of CD26/DPP IV during the development of colitis (AU)


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Assuntos
Animais , Masculino , Feminino , Camundongos , Colite Ulcerativa/metabolismo , Colo/metabolismo , Modelos Animais de Doenças , Mucosa Intestinal/metabolismo , Infiltração de Neutrófilos , Dipeptidil Peptidase 4/metabolismo , Progressão da Doença , Regulação da Expressão Gênica , Remissão Espontânea , Tamanho do Órgão , Peroxidase/metabolismo , Biomarcadores , Fator de Transcrição RelA , Organismos Livres de Patógenos Específicos
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