Lipopolysaccharide-induced serotonin transporter up-regulation involves PKG-I and p38MAPK activation partially through A3 adenosine receptor

Zhao, Rui; Wang, Shoubao; Huang, Zhonglin; Zhang, Li; Yang, Xiuying; Bai, Xiaoyu; Zhou, Dan; Qin, Zhizhen; Du, Guanhua

doi:10.5582/bst.2015.01168

Cited by 6 publications

(7 citation statements)

References 32 publications

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“…Previously, it has been demonstrated that both lipopolysaccharides (LPS) and proinflammatory cytokines increase monoamine transporter (SERT, DAT, NET) trafficking and function [74,75,76,77]. There is a growing body of evidence that the influence of proinflammatory cytokines on SERT trafficking is p38 MAPK-dependent, resulting in increased SERT availability and more reuptake of serotonin [74,75,76,77,78,79,80,81,82]. Other kinases, however, may be associated with SERT regulation, such as Protein Kinase C (PKC), ERK1/2, phosphatidylinositol 3-Kinase/Akt, and adenosine [76,79,83].…”

Section: Discussionmentioning

confidence: 99%

Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression

et al. 2019

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Juvenile idiopathic arthritis (JIA) represents joint inflammation with an unknown cause that starts before the age of 16, resulting in stiff and painful joints. In addition, JIA patients often report symptoms of sickness behavior. Recent animal studies suggest that proinflammatory cytokines produce sickness behavior by increasing the activity of indoleamine-2,3-dioxygenase (IDO) and guanosinetriphosphate–cyclohydrolase-1 (GTP–CH1). Here, it is hypothesized that inflammation in JIA patients enhances the enzymatic activity of IDO and GTP-CH1 and decreases the co-factor tetrahydrobiopterin (BH4). These compounds play a crucial role in the synthesis and metabolism of neurotransmitters. The aim of our study was to reveal whether inflammation affects both the GTP-CH1 and IDO pathway in JIA patients. Serum samples were collected from twenty-four JIA patients. In these samples, the concentrations of tryptophan (TRP), kynurenine (KYN), tyrosine (TYR), neopterin, and phenylalanine (PHE) were measured. An HPLC method with electrochemical detection was developed to quantify tryptophan, kynurenine, and tyrosine. Neopterin and phenylalanine were quantified by ELISA. The KYN/TRP ratio was measured as an index of IDO activity, while the PHE/TYR ratio was measured as an index of BH4 activity. Neopterin concentrations were used as an indirect measure of GTP-CH1 activity. JIA patients with high disease activity showed higher levels of both neopterin and kynurenine, and a higher ratio of both KYN/TRP and PHE/TYR and lower tryptophan levels than clinically inactive patients. Altogether, these data support our hypothesis that inflammation increases the enzymatic activity of both IDO and GTP-CH1 but decreases the efficacy of the co-factor BH4. In the future, animal studies are needed to investigate whether inflammation-induced changes in these enzymatic pathways and co-factor BH4 lower the levels of the brain neurotransmitters glutamate, noradrenaline, dopamine, serotonin, and melatonin, and consequently, whether they may affect fatigue, cognition, anxiety, and depression. Understanding of these complex neuroimmune interactions provides new possibilities for Pharma-Food interventions to improve the quality of life of patients suffering from chronic inflammation.

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Section: Discussionmentioning

confidence: 99%

Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression

et al. 2019

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“…It is a known fact that LPS binds to toll-like receptor 4 (TLR4) on macrophages, astrocytes, and microglia to produce proinflammatory cytokines, such as IL-1, IL-6 and TNF-α [ 12 , 29 , 30 ]. It has been demonstrated that both LPS and proinflammatory cytokines increase monoamine transporter trafficking and function [ 16 , 24 , 31 , 32 , 33 ] (see Figure 3 ). There is growing body of evidence that this process is p38 MAPK-dependent [ 16 , 17 , 34 , 35 , 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although, also other mechanisms than p38 MAPK have been proposed in the PFC [ 24 ]. In addition, other kinases may be associated with SERT regulation, such as Protein Kinase C, ERK1/2, phosphatidylinositol 3-Kinase/Akt and adenosine [ 31 , 34 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Bacterial Lipopolysaccharide Increases Serotonin Metabolism in Both Medial Prefrontal Cortex and Nucleus Accumbens in Male Wild Type Rats, but Not in Serotonin Transporter Knockout Rats

et al. 2018

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It is well known that bacterial lipopolysaccharides (LPS) both increases proinflammatory cytokines and produces sickness behavior, including fatigue and anhedonia (i.e., the inability to experience pleasure). Previously, we have shown that intraperitoneally (i.p.) administered LPS increased extracellular monoamine metabolite levels in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), which was completely, or at least partly, prevented by pretreatment with a triple reuptake inhibitor that also blocks the serotonin (5-HT) transporter (SERT). This suggests indirectly, that LPS may enhance SERT transporter activity, and consequently, increase removal of 5-HT from the synaptic cleft, and increase metabolism of 5-HT. In the present study, we focus more specifically on the role of SERT in this increased metabolism by using rats, that differ in SERT expression. Therefore, the effects of an intraperitoneal LPS injection on extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were investigated by in vivo microdialysis in the NAc and mPFC of wild type (SERT+/+), heterozygous (SERT+/−) and knockout (SERT−/−) rats. Here, we show that LPS-induced 5-HIAA formation in male rats, is significantly increased in SERT+/+ rats in both the NAc and mPFC, whereas this increase is partly or totally abolished in SERT+/− and SERT−/− rats, respectively. Thus, the present study supports the hypothesis that systemic LPS in male rats increases SERT function and consequently enhances 5-HT uptake and metabolism in both the NAc and mPFC.

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“…Immunofluorescent staining of RXRα and SphK2 was performed as previously described [38]. HCT-116 or HCT-116 Sphk2 cells (2.5 × 10 4 ) were seeded onto 12-mm glass coverslips in 24-well plates.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination

et al. 2017

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The resistance mechanisms that limit the efficacy of retinoid therapy in cancer are poorly understood. Sphingosine kinase 2 (SphK2) is a highly conserved enzyme that is mainly located in the nucleus and endoplasmic reticulum. Unlike well-studied sphingosine kinase 1 (SphK1) located in the cytosol, little has yet understood the functions of SphK2. Here we show that SphK2 overexpression contributes to the resistance of all-trans retinoic acid (ATRA) therapy in colon cancer through rapid degradation of cytoplasmic retinoid X receptor α (RXRα) by lysine 48 (K48)- and lysine 63 (K63)-based polyubiquitination. Human colonic adenocarcinoma HCT-116 cells transfected with SphK2 (HCT-116Sphk2 cells) demonstrate resistance to ATRA therapy as determined by in vitro and in vivo assays. Sphk2 overexpression increases the ATRA-induced nuclear RXRα export to cytoplasm and then rapidly degrades RXRα through the polyubiquitination pathway. We further show that Sphk2 activates the ubiquitin-proteasome system through the signal mechanisms of (1) K48-linked proteosomal degradation and (2) K63-linked ubiquitin-dependent autophagic degradation. These results provide new insights into the biological functions of Sphk2 and the molecular mechanisms that underlie the Sphk2-mediated resistance to retinoid therapy.

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Lipopolysaccharide-induced serotonin transporter up-regulation involves PKG-I and p38MAPK activation partially through A3 adenosine receptor

Cited by 6 publications

References 32 publications

Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression

Juvenile Arthritis Patients Suffering from Chronic Inflammation Have Increased Activity of Both IDO and GTP-CH1 Pathways But Decreased BH4 Efficacy: Implications for Well-Being, Including Fatigue, Cognitive Impairment, Anxiety, and Depression

Bacterial Lipopolysaccharide Increases Serotonin Metabolism in Both Medial Prefrontal Cortex and Nucleus Accumbens in Male Wild Type Rats, but Not in Serotonin Transporter Knockout Rats

Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination

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