The Antidepressant Effects of Gm-Csf Are Mediated by the Reduction of Tlr4/Nf-Kb-Induced Ido Expression Publisher Pubmed



Hemmati S^{1, 2, 3} ; Sadeghi MA^{1, 2, 3} ; Mohammad Jafari R¹ ; Yousefimanesh H^{1, 2} ; Dehpour AR^{1, 4}
Source: Journal of Neuroinflammation Published:2019

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-KB 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-KB signaling pathway, we measured levels ofpNF-KB 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-KB (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-KB in the treated mice. © 2019 The Author(s).