Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2015 |
| Outros Autores: | , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/13389 |
Resumo: | Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil. |
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Borges, Perla VillaniMoret, Katelim HottzMonteiro, Clarissa Menezes MayaSilva, Franklin SouzaAlves, Carlos RobertoBatista, Paulo RicardoCaffarena, Ernesto RaúlPacheco, PatríciaHenriques, Maria das GraçasPenido, Carmen2016-03-29T16:33:08Z2016-03-29T16:33:08Z2015BORGES, Perla Villani; et al. Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages. Molecular Pharmacology, v.88,p.949-961, 2015.0026-895Xhttps://www.arca.fiocruz.br/handle/icict/1338910.1124/mol.115.0989701521-0111engAmerican Society for Pharmacology and Experimental Therapeutics (ASPET)Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophagesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sérgio Arouca. PROCC. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sérgio Arouca. PROCC. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil.Recognition of bacterial lipopolysaccharide (LPS) by innate immune system is mediated by the cluster of differentiation 14/ Toll-like receptor 4/myeloid differentiation protein 2 (MD-2) complex. In this study, we investigated the modulatory effect of gedunin, a limonoid from species of the Meliaceae family described as a heat shock protein Hsp90 inhibitor, on LPS-induced response in immortalized murine macrophages. The pretreatment of wild-type (WT) macrophages with gedunin (0.01–100 mM, noncytotoxic concentrations) inhibited LPS (50 ng/ml)–induced calcium influx, tumor necrosis factor-a, and nitric oxide production in a concentration-dependent manner. The selective effect of gedunin on MyD88-adapter–like/myeloid differentiation primary response 88– and TRIF-related adaptor molecule/TIR domain–containing adapter-inducing interferon-b–dependent signaling pathways was further investigated. The pretreatment of WT, TIR domain–containing adapter-inducing interferon-b knockout, and MyD88 adapter–like knockout macrophages with gedunin (10 mM) significantly inhibited LPS (50 ng/ml)– induced tumor necrosis factor-a and interleukin-6 production, at 6 hours and 24 hours, suggesting that gedunin modulates a common event between both signaling pathways. Furthermore, gedunin (10 mM) inhibited LPS-induced prostaglandin E2 production, cyclooxygenase-2 expression, and nuclear factor kB translocation into the nucleus of WT macrophages, demonstrating a wide-range effect of this chemical compound. In addition to the ability to inhibit LPS-induced proinflammatory mediators, gedunin also triggered anti-inflammatory factors interleukin-10, heme oxygenase-1, and Hsp70 in macrophages stimulated or not with LPS. In silico modeling studies revealed that gedunin efficiently docked into the MD-2 LPS binding site, a phenomenon further confirmed by surface plasmon resonance. Our results reveal that, in addition to Hsp90 modulation, gedunin acts as a competitive inhibitor of LPS, blocking the formation of the Toll-like receptor 4/MD-2/LPS complex.MyeloidLipopolysaccharidePharmacologyMacrophagesMielóideMacrófagosAntígenos CD14Farmacologiainfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/13389/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALclarissa_monteiro_etal_IOC_2015.pdfclarissa_monteiro_etal_IOC_2015.pdfapplication/pdf1467934https://www.arca.fiocruz.br/bitstream/icict/13389/2/clarissa_monteiro_etal_IOC_2015.pdf9527ee60710554f3f27f62d4cc40a38aMD52TEXTclarissa_monteiro_etal_IOC_2015.pdf.txtclarissa_monteiro_etal_IOC_2015.pdf.txtExtracted 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| dc.title.pt_BR.fl_str_mv |
Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages |
| title |
Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages |
| spellingShingle |
Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages Borges, Perla Villani Myeloid Lipopolysaccharide Pharmacology Macrophages Mielóide Macrófagos Antígenos CD14 Farmacologia |
| title_short |
Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages |
| title_full |
Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages |
| title_fullStr |
Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages |
| title_full_unstemmed |
Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages |
| title_sort |
Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages |
| author |
Borges, Perla Villani |
| author_facet |
Borges, Perla Villani Moret, Katelim Hottz Monteiro, Clarissa Menezes Maya Silva, Franklin Souza Alves, Carlos Roberto Batista, Paulo Ricardo Caffarena, Ernesto Raúl Pacheco, Patrícia Henriques, Maria das Graças Penido, Carmen |
| author_role |
author |
| author2 |
Moret, Katelim Hottz Monteiro, Clarissa Menezes Maya Silva, Franklin Souza Alves, Carlos Roberto Batista, Paulo Ricardo Caffarena, Ernesto Raúl Pacheco, Patrícia Henriques, Maria das Graças Penido, Carmen |
| author2_role |
author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Borges, Perla Villani Moret, Katelim Hottz Monteiro, Clarissa Menezes Maya Silva, Franklin Souza Alves, Carlos Roberto Batista, Paulo Ricardo Caffarena, Ernesto Raúl Pacheco, Patrícia Henriques, Maria das Graças Penido, Carmen |
| dc.subject.en.pt_BR.fl_str_mv |
Myeloid Lipopolysaccharide Pharmacology Macrophages |
| topic |
Myeloid Lipopolysaccharide Pharmacology Macrophages Mielóide Macrófagos Antígenos CD14 Farmacologia |
| dc.subject.decs.pt_BR.fl_str_mv |
Mielóide Macrófagos Antígenos CD14 Farmacologia |
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Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil. |
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2015 |
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2015 |
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2016-03-29T16:33:08Z |
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2016-03-29T16:33:08Z |
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BORGES, Perla Villani; et al. Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages. Molecular Pharmacology, v.88,p.949-961, 2015. |
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https://www.arca.fiocruz.br/handle/icict/13389 |
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0026-895X |
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10.1124/mol.115.098970 |
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1521-0111 |
| identifier_str_mv |
BORGES, Perla Villani; et al. Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages. Molecular Pharmacology, v.88,p.949-961, 2015. 0026-895X 10.1124/mol.115.098970 1521-0111 |
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American Society for Pharmacology and Experimental Therapeutics (ASPET) |
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