The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression
Abstract 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 granulo...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-06-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-019-1509-1 |
| _version_ | 1819298138679148544 |
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| author | Sara Hemmati Mohammad Amin Sadeghi Razieh Mohammad Jafari Hasan Yousefi-Manesh Ahmad Reza Dehpour |
| author_facet | Sara Hemmati Mohammad Amin Sadeghi Razieh Mohammad Jafari Hasan Yousefi-Manesh Ahmad Reza Dehpour |
| author_sort | Sara Hemmati |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-24T05:25:08Z |
| format | Article |
| id | doaj.art-60f1fe8639894cc5be0beeac1c5b9c36 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-24T05:25:08Z |
| publishDate | 2019-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-60f1fe8639894cc5be0beeac1c5b9c362022-12-21T17:13:21ZengBMCJournal of Neuroinflammation1742-20942019-06-0116111010.1186/s12974-019-1509-1The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expressionSara Hemmati0Mohammad Amin Sadeghi1Razieh Mohammad Jafari2Hasan Yousefi-Manesh3Ahmad Reza Dehpour4Experimental Medicine Research Center, Tehran University of Medical SciencesExperimental Medicine Research Center, Tehran University of Medical SciencesExperimental Medicine Research Center, Tehran University of Medical SciencesExperimental Medicine Research Center, Tehran University of Medical SciencesExperimental Medicine Research Center, Tehran University of Medical SciencesAbstract 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.http://link.springer.com/article/10.1186/s12974-019-1509-1DepressionLipopolysaccharideGranulocyte-macrophage stimulating factorIndoleamine 2, 3-dioxygenaseNF-ĸBInflammation-induced depression |
| spellingShingle | Sara Hemmati Mohammad Amin Sadeghi Razieh Mohammad Jafari Hasan Yousefi-Manesh Ahmad Reza Dehpour The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression Journal of Neuroinflammation Depression Lipopolysaccharide Granulocyte-macrophage stimulating factor Indoleamine 2, 3-dioxygenase NF-ĸB Inflammation-induced depression |
| 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 qb induced ido expression |
| topic | Depression Lipopolysaccharide Granulocyte-macrophage stimulating factor Indoleamine 2, 3-dioxygenase NF-ĸB Inflammation-induced depression |
| url | http://link.springer.com/article/10.1186/s12974-019-1509-1 |
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