Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/13389
Title: Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages
Authors: 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
Affilliation: 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. 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.
Abstract: 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.
Keywords: Myeloid
Lipopolysaccharide
Pharmacology
Macrophages
DeCS: Mielóide
Macrófagos
Antígenos CD14
Farmacologia
Issue Date: 2015
Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)
Citation: 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.
DOI: 10.1124/mol.115.098970
ISSN: 0026-895X
Copyright: open access
Appears in Collections:IOC - Artigos de Periódicos

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