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1.
J Cell Physiol ; 230(4): 863-74, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25294243

RESUMO

The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome is a reactive oxygen species-sensitive multiprotein complex that regulates IL-1ß maturation via caspase-1. It also plays an important role in the pathogenesis of inflammation-related disease. Cyclooxygenase-2 (COX-2) is induced by inflammatory stimuli and contributes to the pathogenesis of inflammation-related diseases. However, there is currently little known about the relationship between COX-2 and the NLRP3 inflammasome. Here, we describe a novel role for COX-2 in regulating the activation of the NLRP3 inflammasome. NLRP3 inflammasome-derived IL-1ß secretion and pyroptosis in macrophages were reduced by pharmaceutical inhibition or genetic knockdown of COX-2. COX-2 catalyzes the synthesis of prostaglandin E2 and increases IL-1ß secretion. Conversely, pharmaceutical inhibition or genetic knockdown of prostaglandin E2 receptor 3 reduced IL-1ß secretion. The underlying mechanisms for the COX-2-mediated increase in NLRP3 inflammasome activation were determined to be the following: (1) enhancement of lipopolysaccharide-induced proIL-1ß and NLRP3 expression by increasing NF-κB activation and (2) enhancement of the caspase-1 activation by increasing damaged mitochondria, mitochondrial reactive oxygen species production and release of mitochondrial DNA into cytosol. Furthermore, inhibition of COX-2 in mice in vivo with celecoxib reduced serum levels of IL-1ß and caspase-1 activity in the spleen and liver in response to lipopolysaccharide (LPS) challenge. These findings provide new insights into how COX-2 regulates the activation of the NLRP3 inflammasome and suggest that it may be a new potential therapeutic target in NLRP3 inflammasome-related diseases.


Assuntos
Proteínas de Transporte/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inflamassomos/metabolismo , Inflamação/metabolismo , Interleucina-1beta/biossíntese , Animais , Caspase 1/metabolismo , Regulação da Expressão Gênica/fisiologia , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Camundongos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
2.
Free Radic Biol Med ; 73: 260-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24858719

RESUMO

Inflammatory reactions and oxidative stress are implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS), a common chronic kidney disease with relatively poor prognosis and unsatisfactory treatment regimens. Previously, we showed that osthole, a coumarin compound isolated from the seeds of Cnidium monnieri, can inhibit reactive oxygen species generation, NF-κB activation, and cyclooxygenase-2 expression in lipopolysaccharide-activated macrophages. In this study, we further evaluated its renoprotective effect in a mouse model of accelerated FSGS (acFSGS), featuring early development of proteinuria, followed by impaired renal function, glomerular epithelial cell hyperplasia lesions (a sensitive sign that precedes the development of glomerular sclerosis), periglomerular inflammation, and glomerular hyalinosis/sclerosis. The results show that osthole significantly prevented the development of the acFSGS model in the treated group of mice. The mechanisms involved in the renoprotective effects of osthole on the acFSGS model were mainly a result of an activated Nrf2-mediated antioxidant pathway in the early stage (proteinuria and ischemic collapse of the glomeruli) of acFSGS, followed by a decrease in: (1) NF-κB activation and COX-2 expression as well as PGE2 production, (2) podocyte injury, and (3) apoptosis. Our data support that targeting the Nrf2 antioxidant pathway may justify osthole being established as a candidate renoprotective compound for FSGS.


Assuntos
Apoptose/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Cumarínicos/farmacologia , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Cnidium/metabolismo , Ciclo-Oxigenase 2/biossíntese , Dinoprostona/biossíntese , Modelos Animais de Doenças , Feminino , Glomerulosclerose Segmentar e Focal/prevenção & controle , Glutationa Peroxidase/metabolismo , Heme Oxigenase-1/biossíntese , Inflamação/tratamento farmacológico , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Preparações de Plantas/farmacologia , Podócitos/efeitos dos fármacos , Podócitos/patologia , Proteinúria/tratamento farmacológico , Proteinúria/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo
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