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The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression
BACKGROUND: Indoleamine 2, 3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway. This pathway has been implicated in the pathophysiology of inflammation-induced depression in which conventional antidepressants are not effective. It has been reported that granulocyte-mac...
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/PMC6545198/ https://www.ncbi.nlm.nih.gov/pubmed/31153376 http://dx.doi.org/10.1186/s12974-019-1509-1 |
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author | Hemmati, Sara Sadeghi, Mohammad Amin Mohammad Jafari, Razieh Yousefi-Manesh, Hasan Dehpour, Ahmad Reza |
author_facet | Hemmati, Sara Sadeghi, Mohammad Amin Mohammad Jafari, Razieh Yousefi-Manesh, Hasan Dehpour, Ahmad Reza |
author_sort | Hemmati, Sara |
collection | PubMed |
description | BACKGROUND: Indoleamine 2, 3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway. This pathway has been implicated in the pathophysiology of inflammation-induced depression in which conventional antidepressants are not effective. It has been reported that granulocyte-macrophage stimulating factor (GM-CSF) could interfere with the induction of IDO in septic patients. We hypothesized that GM-CSF could exert antidepressant effects through IDO downregulation in a model for acute inflammation-induced depression. METHODS: To produce the model, lipopolysaccharide (LPS) (0.83 mg/kg) was administered intraperitoneally to mice. It has been well documented that LPS mediates IDO overexpression through TLR4/NF-ĸB signaling. In the treatment group, mice received GM-CSF (30 μg/kg, i.p.) thirty minutes prior to LPS injection. A validated selective serotonin reuptake inhibitor, fluoxetine (30 mg/kg i.p.), was also administered to an experimental group 30 min prior to LPS. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. To confirm that GM-CSF interferes with IDO induction in LPS treated mice, real-time PCR was used to quantify IDO mRNA expression. Furthermore, in order to study whether GM-CSF inhibits the TLR4/NF-ĸB signaling pathway, we measured levels ofpNF-ĸB and TLR4 by western blotting. RESULTS: GM-CSF demonstrated significant antidepressant activity in the presence of LPS on immobility (p < .001) and latency (p = .010) times in the forced swim test. In contrast, fluoxetine did not show any antidepressant activity on either immobility (p = .918) or latency (p = .566) times. Furthermore, GM-CSF inhibited the increase in IDO mRNA (p = .032) and protein (p = .016) expression as a result of LPS administration. A similar trend was observed for TLR4 (p = .042) and pNF-ĸB (p = .026) expression as both proteins showed reduced expression levels in the GM-CSF-pretreated group compared to the untreated (LPS) group. CONCLUSION: Our results propose a promising antidepressant effect for GM-CSF possibly through the downregulation of IDO expression. This remedying effect of GM-CSF could be attributed to decreased amounts of TLR4 and active NF-ĸB in the treated mice. |
format | Online Article Text |
id | pubmed-6545198 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-65451982019-06-05 The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression Hemmati, Sara Sadeghi, Mohammad Amin Mohammad Jafari, Razieh Yousefi-Manesh, Hasan Dehpour, Ahmad Reza J Neuroinflammation Research BACKGROUND: Indoleamine 2, 3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway. This pathway has been implicated in the pathophysiology of inflammation-induced depression in which conventional antidepressants are not effective. It has been reported that granulocyte-macrophage stimulating factor (GM-CSF) could interfere with the induction of IDO in septic patients. We hypothesized that GM-CSF could exert antidepressant effects through IDO downregulation in a model for acute inflammation-induced depression. METHODS: To produce the model, lipopolysaccharide (LPS) (0.83 mg/kg) was administered intraperitoneally to mice. It has been well documented that LPS mediates IDO overexpression through TLR4/NF-ĸB signaling. In the treatment group, mice received GM-CSF (30 μg/kg, i.p.) thirty minutes prior to LPS injection. A validated selective serotonin reuptake inhibitor, fluoxetine (30 mg/kg i.p.), was also administered to an experimental group 30 min prior to LPS. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. To confirm that GM-CSF interferes with IDO induction in LPS treated mice, real-time PCR was used to quantify IDO mRNA expression. Furthermore, in order to study whether GM-CSF inhibits the TLR4/NF-ĸB signaling pathway, we measured levels ofpNF-ĸB and TLR4 by western blotting. RESULTS: GM-CSF demonstrated significant antidepressant activity in the presence of LPS on immobility (p < .001) and latency (p = .010) times in the forced swim test. In contrast, fluoxetine did not show any antidepressant activity on either immobility (p = .918) or latency (p = .566) times. Furthermore, GM-CSF inhibited the increase in IDO mRNA (p = .032) and protein (p = .016) expression as a result of LPS administration. A similar trend was observed for TLR4 (p = .042) and pNF-ĸB (p = .026) expression as both proteins showed reduced expression levels in the GM-CSF-pretreated group compared to the untreated (LPS) group. CONCLUSION: Our results propose a promising antidepressant effect for GM-CSF possibly through the downregulation of IDO expression. This remedying effect of GM-CSF could be attributed to decreased amounts of TLR4 and active NF-ĸB in the treated mice. BioMed Central 2019-06-01 /pmc/articles/PMC6545198/ /pubmed/31153376 http://dx.doi.org/10.1186/s12974-019-1509-1 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 Hemmati, Sara Sadeghi, Mohammad Amin Mohammad Jafari, Razieh Yousefi-Manesh, Hasan Dehpour, Ahmad Reza The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression |
title | The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression |
title_full | The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression |
title_fullStr | The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression |
title_full_unstemmed | The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression |
title_short | The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression |
title_sort | antidepressant effects of gm-csf are mediated by the reduction of tlr4/nf-ĸb-induced ido expression |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545198/ https://www.ncbi.nlm.nih.gov/pubmed/31153376 http://dx.doi.org/10.1186/s12974-019-1509-1 |
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