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| [PMID]: | 28619997 |
| [Au] Autor: | Chen Y; Huang W; Yang M; Xin G; Cui W; Xie Z; Silverstein RL |
| [Ad] Endereço: | From the Blood Research Institute, Blood Center of Wisconsin, Milwaukee (Y.C., W.H., M.Y., G.X., W.C., R.L.S.); Department of Cell Biology, Neurobiology and Anatomy (M.Y., R.L.S.) and Department of Medicine (R.L.S.), Medical College of Wisconsin, Milwaukee; and Departments of Medicine, Pharmacology |
| [Ti] Título: | Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase. |
| [So] Source: | Arterioscler Thromb Vasc Biol;37(8):1462-1469, 2017 Aug. | | [Is] ISSN: | 1524-4636 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | OBJECTIVE: Circulating levels of cardiotonic steroids (CTS) are elevated in various chronic inflammatory conditions, but the role of CTS in inflammation remains largely unknown. We have previously shown that the CTS ouabain stimulates proinflammatory responses in murine macrophages. In this study, we aim to explore the mechanism how CTS induce proinflammatory responses in primary murine and human macrophages. APPROACH AND RESULTS: Using both murine peritoneal macrophages and human monocyte-derived macrophages, we demonstrated that ouabain activated NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), leading to proinflammatory cytokine (eg, MCP-1 [monocyte chemotactic protein 1], TNF-α [tumor necrosis factor-α], IL-1ß [interleukin-1ß], and IL-6) production. By applying siRNA techniques and murine peritoneal macrophages isolated from genetically modified mice, we showed that macrophages partially deficient in Na/K-ATPase, the receptor for CTS, or fully deficient in the scavenger receptor CD36 or TLR4 (Toll-like receptor) were resistant to ouabain-induced NF-κB activation, suggesting an indispensable role of these 3 receptors in this pathway. Mechanistically, this effect of ouabain was independent of the ion transport function of the Na/K-ATPase. Instead, ouabain stimulated a signaling complex, including Na/K-ATPase, CD36, and TLR4. Subsequently, TLR4 recruited MyD88 adaptor protein for NF-κB activation. Furthermore, intraperitoneal injection of ouabain into mice specifically recruited Ly6C CCR2 monocyte subtypes to the peritoneal cavities, indicating that the CTS ouabain triggers inflammation in vivo. CONCLUSIONS: CTS activate NF-κB leading to proinflammatory cytokine production in primary macrophages through a signaling complex, including CD36, TLR4, and Na/K-ATPase. These findings warrant further studies on endogenous CTS in chronic inflammatory diseases, such as atherosclerosis. |
| [Mh] Termos MeSH primário: |
Antígenos CD36/metabolismo
Cardiotônicos/toxicidade
Mediadores da Inflamação/metabolismo
Inflamação/induzido quimicamente
Macrófagos Peritoneais/efeitos dos fármacos
Ouabaína/toxicidade
ATPase Trocadora de Sódio-Potássio/metabolismo
Receptor 4 Toll-Like/metabolismo
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| [Mh] Termos MeSH secundário: |
Animais
Antígenos CD36/deficiência
Antígenos CD36/genética
Células Cultivadas
Citocinas/metabolismo
Relação Dose-Resposta a Droga
Ativação Enzimática
Feminino
Inflamação/enzimologia
Inflamação/genética
Macrófagos Peritoneais/enzimologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fator 88 de Diferenciação Mieloide/metabolismo
NF-kappa B/genética
NF-kappa B/metabolismo
Interferência de RNA
Transdução de Sinais/efeitos dos fármacos
ATPase Trocadora de Sódio-Potássio/deficiência
ATPase Trocadora de Sódio-Potássio/genética
Fatores de Tempo
Transfecção
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (CD36 Antigens); 0 (Cardiotonic Agents); 0 (Cytokines); 0 (Inflammation Mediators); 0 (MYD88 protein, human); 0 (Myd88 protein, mouse); 0 (Myeloid Differentiation Factor 88); 0 (NF-kappa B); 0 (TLR4 protein, human); 0 (Tlr4 protein, mouse); 0 (Toll-Like Receptor 4); 5ACL011P69 (Ouabain); EC 3.6.1.- (ATP1A1 protein, human); EC 3.6.3.9 (Atp1a1 protein, mouse); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase) |
| [Em] Mês de entrada: | 1708 |
| [Cu] Atualização por classe: | 171116 |
[Lr] Data última revisão:
| 171116 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 170617 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1161/ATVBAHA.117.309444 |
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