| Author | Borges, Perla Villani | |
| Author | Moret, Katelim Hottz | |
| Author | Monteiro, Clarissa Menezes Maya | |
| Author | Silva, Franklin Souza | |
| Author | Alves, Carlos Roberto | |
| Author | Batista, Paulo Ricardo | |
| Author | Caffarena, Ernesto Raúl | |
| Author | Pacheco, Patrícia | |
| Author | Henriques, Maria das Graças | |
| Author | Penido, Carmen | |
| Access date | 2016-03-29T16:33:08Z | |
| Available date | 2016-03-29T16:33:08Z | |
| Document date | 2015 | |
| 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. | pt_BR |
| ISSN | 0026-895X | |
| URI | https://www.arca.fiocruz.br/handle/icict/13389 | |
| Language | eng | pt_BR |
| Publisher | American Society for Pharmacology and Experimental Therapeutics (ASPET) | pt_BR |
| Rights | open access | |
| Title | Gedunin Binds to Myeloid Differentiation Protein 2 and Impairs Lipopolysaccharide-Induced Toll-Like Receptor 4 Signaling in Macrophages | pt_BR |
| Type | Article | |
| DOI | 10.1124/mol.115.098970 | |
| 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. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sérgio Arouca. PROCC. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sérgio Arouca. PROCC. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Farmanguinhos. Laboratório de Farmacologia Aplicada. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | Myeloid | pt_BR |
| Subject | Lipopolysaccharide | pt_BR |
| Subject | Pharmacology | pt_BR |
| Subject | Macrophages | pt_BR |
| DeCS | Mielóide | pt_BR |
| DeCS | Macrófagos | pt_BR |
| DeCS | Antígenos CD14 | pt_BR |
| DeCS | Farmacologia | pt_BR |
| e-ISSN | 1521-0111 | |
