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1.
Am J Physiol Renal Physiol ; 322(2): F164-F174, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34894725

RESUMO

Interleukin (IL)-1 receptor type 1 (IL-1R1) activation triggers a proinflammatory signaling cascade that can exacerbate kidney injury. However, the functions of podocyte IL-1R1 in glomerular disease remain unclear. To study the role of IL-1R1 signaling in podocytes, we selectively ablated podocyte IL-1R1 in mice (PKO mice). We then subjected PKO mice and wild-type controls to two glomerular injury models: nephrotoxic serum (NTS)- and adriamycin-induced nephropathy. Surprisingly, we found that IL-1R1 activation in podocytes limited albuminuria and podocyte injury during NTS- and adriamycin-induced nephropathy. Moreover, deletion of IL-1R1 in podocytes drove podocyte apoptosis and glomerular injury through diminishing Akt activation. Activation of Akt signaling abrogated the differences in albuminuria and podocyte injury between wild-type and PKO mice during NTS. Thus, IL-1R1 signaling in podocytes limits susceptibility to glomerular injury via an Akt-dependent signaling pathway. These data identify an unexpected protective role for IL-1R1 signaling in podocytes in the pathogenesis of glomerular disease.NEW & NOTEWORTHY The present study establishes that activation of the receptor for interleukin-1 limits susceptibility to damage to the kidney glomerulus in preclinical mouse models by stimulating Akt signaling cascades inside the podocyte.


Assuntos
Glomerulonefrite/metabolismo , Podócitos/metabolismo , Proteinúria/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Doxorrubicina , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/patologia , Glomerulonefrite/prevenção & controle , Humanos , Interleucina-1beta/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Camundongos da Linhagem 129 , Camundongos Knockout , Podócitos/efeitos dos fármacos , Podócitos/patologia , Proteinúria/induzido quimicamente , Proteinúria/patologia , Proteinúria/prevenção & controle , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Tipo I de Interleucina-1/agonistas , Receptores Tipo I de Interleucina-1/genética , Transdução de Sinais
2.
Mol Hum Reprod ; 27(12)2021 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-34915564

RESUMO

Decorin, a small leucine-rich proteoglycan produced by decidual cells restrains trophoblast differentiation, migration and invasiveness of extra-villous trophoblast cells. Decidual overproduction of decorin is associated with preeclampsia, and elevated decorin levels in maternal plasma are a predictive biomarker of preeclampsia. Furthermore, decorin plays an autocrine role in maturation of human endometrial stromal cells into decidual cells. Thus, a balanced decorin production by the decidua is critical for healthy pregnancy. However, the molecular mechanisms regulating decorin production by the decidua are unclear. Interleukin-1 beta is an inflammation-associated multi-functional cytokine, and is reported to induce decidualization in primates. Hence, the present study was designed: (i) to test if exogenous Interleukin-1 beta stimulated decorin production by human endometrial stromal cells; and if so, (ii) to identify the cellular source of Interleukin-1 beta in first trimester decidual tissue; (iii) to identify the downstream molecular partners in Interleukin-1 beta mediated decorin production by human endometrial stromal cells. Results revealed that (i) amongst multiple pro-inflammatory cytokines tested, Interleukin-1 beta alone stimulated decorin production by these cells; (ii) both macrophages and decidual cells in first trimester decidua produced Interleukin-1 beta; (iii) Interleukin-1 beta mediated decorin production was dependent on Interleukin-1 receptor activation, followed by activation and nuclear translocation of nuclear factor kappa B and its binding to the decorin promoter. These results reveal that Interleukin-1 beta plays a novel role in inducing decorin production by human endometrial stromal cells by activating nuclear factor kappa B.


Assuntos
Decídua/efeitos dos fármacos , Decorina/metabolismo , Interleucina-1beta/farmacologia , Macrófagos/efeitos dos fármacos , Receptores Tipo I de Interleucina-1/agonistas , Células Estromais/efeitos dos fármacos , Transporte Ativo do Núcleo Celular , Sítios de Ligação , Linhagem Celular , Decídua/metabolismo , Decorina/genética , Feminino , Humanos , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , NF-kappa B/metabolismo , Gravidez , Primeiro Trimestre da Gravidez , Regiões Promotoras Genéticas , Receptores Tipo I de Interleucina-1/metabolismo , Células Estromais/metabolismo , Regulação para Cima
3.
PLoS Pathog ; 11(9): e1005155, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26367131

RESUMO

Viral fulminant hepatitis (FH) is a severe disease with high mortality resulting from excessive inflammation in the infected liver. Clinical interventions have been inefficient due to the lack of knowledge for inflammatory pathogenesis in the virus-infected liver. We show that wild-type mice infected with murine hepatitis virus strain-3 (MHV-3), a model for viral FH, manifest with severe disease and high mortality in association with a significant elevation in IL-1ß expression in the serum and liver. Whereas, the viral infection in IL-1ß receptor-I deficient (IL-1R1-/-) or IL-1R antagonist (IL-1Ra) treated mice, show reductions in virus replication, disease progress and mortality. IL-1R1 deficiency appears to debilitate the virus-induced fibrinogen-like protein-2 (FGL2) production in macrophages and CD45+Gr-1high neutrophil infiltration in the liver. The quick release of reactive oxygen species (ROS) by the infected macrophages suggests a plausible viral initiation of NLRP3 inflammasome activation. Further experiments show that mice deficient of p47phox, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit that controls acute ROS production, present with reductions in NLRP3 inflammasome activation and subsequent IL-1ß secretion during viral infection, which appears to be responsible for acquiring resilience to viral FH. Moreover, viral infected animals in deficiencies of NLRP3 and Caspase-1, two essential components of the inflammasome complex, also have reduced IL-1ß induction along with ameliorated hepatitis. Our results demonstrate that the ROS/NLRP3/IL-1ß axis institutes an essential signaling pathway, which is over activated and directly causes the severe liver disease during viral infection, which sheds light on development of efficient treatments for human viral FH and other severe inflammatory diseases.


Assuntos
Proteínas de Transporte/agonistas , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Interleucina-1beta/agonistas , Fígado/virologia , Vírus da Hepatite Murina/fisiologia , Receptores Tipo I de Interleucina-1/agonistas , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Progressão da Doença , Fibrinogênio/metabolismo , Imunidade Inata , Inflamassomos/imunologia , Inflamassomos/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/ultraestrutura , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vírus da Hepatite Murina/efeitos dos fármacos , Vírus da Hepatite Murina/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Células RAW 264.7 , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Receptores Tipo I de Interleucina-1/antagonistas & inibidores , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Análise de Sobrevida
4.
J Clin Invest ; 117(12): 3786-99, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17992263

RESUMO

The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1beta recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1beta production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.


Assuntos
Fator 88 de Diferenciação Mieloide/metabolismo , Pneumonia/metabolismo , Fibrose Pulmonar/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Transdução de Sinais , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Transplante de Medula Óssea , Doença Crônica , Modelos Animais de Doenças , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/farmacologia , Interleucina-8/genética , Interleucina-8/metabolismo , Linfocinas/genética , Linfocinas/metabolismo , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Pneumonia/induzido quimicamente , Pneumonia/genética , Pneumonia/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Receptores Tipo I de Interleucina-1/agonistas , Receptores Tipo I de Interleucina-1/antagonistas & inibidores , Receptores Tipo I de Interleucina-1/genética , Proteínas Recombinantes/farmacologia , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/patologia , Sialoglicoproteínas/genética , Sialoglicoproteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Quimeras de Transplante/genética , Quimeras de Transplante/metabolismo
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