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Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway
BACKGROUND: Neuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation of microglia, the principal immune effector cells of the brain, contributes to neuronal...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637517/ https://www.ncbi.nlm.nih.gov/pubmed/31319868 http://dx.doi.org/10.1186/s12974-019-1538-9 |
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author | Zusso, Morena Lunardi, Valentina Franceschini, Davide Pagetta, Andrea Lo, Rita Stifani, Stefano Frigo, Anna Chiara Giusti, Pietro Moro, Stefano |
author_facet | Zusso, Morena Lunardi, Valentina Franceschini, Davide Pagetta, Andrea Lo, Rita Stifani, Stefano Frigo, Anna Chiara Giusti, Pietro Moro, Stefano |
author_sort | Zusso, Morena |
collection | PubMed |
description | BACKGROUND: Neuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an α,β-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4–myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-κB inflammatory signaling pathway. METHODS: The putative binding mode of five FQs [ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin] to TLR4–MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1β and TNF-α and NF-κB activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4–MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells. RESULTS: CPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-κB in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4–MD-2 complex and decreased the resulting TLR4–MD-2 dimerization in Ba/F3 cells. CONCLUSIONS: These results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-κB signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4–MD-2 complex, a potential key target for controlling neuroinflammation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-019-1538-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6637517 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-66375172019-07-25 Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway Zusso, Morena Lunardi, Valentina Franceschini, Davide Pagetta, Andrea Lo, Rita Stifani, Stefano Frigo, Anna Chiara Giusti, Pietro Moro, Stefano J Neuroinflammation Research BACKGROUND: Neuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an α,β-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4–myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-κB inflammatory signaling pathway. METHODS: The putative binding mode of five FQs [ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin] to TLR4–MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1β and TNF-α and NF-κB activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4–MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells. RESULTS: CPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-κB in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4–MD-2 complex and decreased the resulting TLR4–MD-2 dimerization in Ba/F3 cells. CONCLUSIONS: These results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-κB signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4–MD-2 complex, a potential key target for controlling neuroinflammation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-019-1538-9) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-18 /pmc/articles/PMC6637517/ /pubmed/31319868 http://dx.doi.org/10.1186/s12974-019-1538-9 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Zusso, Morena Lunardi, Valentina Franceschini, Davide Pagetta, Andrea Lo, Rita Stifani, Stefano Frigo, Anna Chiara Giusti, Pietro Moro, Stefano Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway |
title | Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway |
title_full | Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway |
title_fullStr | Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway |
title_full_unstemmed | Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway |
title_short | Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway |
title_sort | ciprofloxacin and levofloxacin attenuate microglia inflammatory response via tlr4/nf-kb pathway |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637517/ https://www.ncbi.nlm.nih.gov/pubmed/31319868 http://dx.doi.org/10.1186/s12974-019-1538-9 |
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