The Dual Role of the ß2-Adrenoreceptor in the Modulation of IL-17 and IFN-γ Production by T Cells in Multiple Sclerosis.

Norepinephrine is a neurotransmitter that also has an immunomodulatory effect and is involved in multiple sclerosis (MS) pathogenesis. This study aimed to clarify the role of the ß2-adrenoreceptor in the norepinephrine-mediated modulation of interleukin-17 (IL-17) and interferon-γ (IFN-γ) production, which play a critical pathogenetic role in MS. CD4+ T cells obtained from twenty-five relapsing-remitting MS patients and sixteen healthy subjects were cultured ex vivo with norepinephrine and/or ß2-adrenoreceptor antagonist or agonist, followed by a cytokine production analysis using ELISA. Norepinephrine suppressed IL-17 and IFN-γ production by the anti-CD3/anti-CD28-microbead-stimulated CD4+ T cells in both groups. Blockade of the ß2-adrenoreceptor with the specific antagonist ICI 118.551 enhanced norepinephrine-mediated IL-17 suppression but decreased its inhibitory effect on IFN-γ production in MS patients. In contrast, the ß2-adrenoreceptor agonist formoterol did not influence norepinephrine's inhibitory effect on cytokine production in both groups. The blockade of the ß2-adrenoreceptor, even in the absence of exogenous norepinephrine, suppressed IL-17 production but did not influence IFN-γ production in both groups. Conversely, ß2-adrenoreceptor activation by formoterol decreased IFN-γ production and did not affect IL-17 production in both groups. These data illustrate the inhibitory effect of norepinephrine on IL-17 and IFN-γ production by CD4+ T cells in MS. The inhibitory effect of norepinephrine on IFN-γ production by CD4+ T cells in MS could be mediated via ß2-adrenoreceptor activation.

The Role of D2-like Dopaminergic Receptor in Dopamine-mediated Modulation of Th17-cells in Multiple Sclerosis.

BACKGROUND: Dopamine is one of the main mediators capable regulate the neuroimmune interaction and is involved in multiple sclerosis (MS) pathogenesis. OBJECTIVE: The aim of this study was to clarify the role of dopamine and its receptors in modulation of Th17-cells in MS. METHODS: 34 relapsing-remitting MS patients and 23 healthy subjects were examined. To assess the effect of dopamine on Th17-cells, CD4+ T-cells were cultured in the presence of dopamine and antagonist or agonist of D1- or D2-like dopaminergic receptors and stimulated with anti-CD3/CD28- microbeads. The levels of cytokines in supernatants were assessed by ELISA. RESULTS: Production of interleukin-17 (IL-17), interferon-γ (IFN-γ), granulocyte-colony stimulating factor (GM-CSF), and IL-21 by CD4+ T-cells as well as dopamine were comparable between the groups. Dopamine suppressed cytokine secretion by activated СD4+ T-cells in both groups. Blockade of D1-like dopaminergic receptor with a specific antagonist SCH23390 did not affect dopaminemediated cytokine suppression. In contrast, blockade of D2-like dopaminergic receptor by sulpiride decreased dopamine's inhibitory effect on IL-17 secretion in both groups and GM-CSF and IL-21 production in MS patients. Blockade of D1-like dopaminergic receptor directly inhibited IL-17, IFN- γ, GM-CSF in both groups and IL-21 production in healthy subjects, while blockade of D2-like dopaminergic receptor had no effect on cytokine secretion. Finally, activation of D2-like dopaminergic receptor with a specific agonist quinpirole decreased cytokine production in both groups. CONCLUSION: These data suggest an inhibitory role of dopamine on Th17-cells in MS, which could be mediated by the activation of the D2-like dopaminergic receptor.

Correlation of Acinetobacter baumannii K144 and K86 capsular polysaccharide structures with genes at the K locus reveals the involvement of a novel multifunctional rhamnosyltransferase for structural synthesis.

Whole genome sequence from Acinetobacter baumannii isolate Ab-46-1632 reveals a novel KL144 capsular polysaccharide (CPS) biosynthesis gene cluster, which carries genes for d-glucuronic acid (D-GlcA) and l-rhamnose (l-Rha) synthesis. The CPS was extracted from Ab-46-1632 and studied by 1H and 13C NMR spectroscopy, including a two-dimensional 1H,13C HMBC experiment and Smith degradation. The CPS was found to have a hexasaccharide repeat unit composed of four l-Rhap residues and one residue each of d-GlcpA and N-acetyl-d-glucosamine (D-GlcpNAc) consistent with sugar synthesis genes present in KL144. The K144 CPS structure was established and found to be related to those of A. baumannii K55, K74, K85, and K86. A comparison of the corresponding gene clusters to KL144 revealed a number of shared glycosyltransferase genes correlating to shared glycosidic linkages in the structures. One from the enzymes, encoded by only KL144 and KL86, is proposed to be a novel multifunctional rhamnosyltransfaerase likely responsible for synthesis of a shared α-l-Rhap-(1 â†’ 2)-α-L-Rhap-(1 â†’ 3)-L-Rhap trisaccharide fragment in the K144 and K86 structures.

The role of 5-HT2B-receptors in fluoxetine-mediated modulation of Th17- and Th1-cells in multiple sclerosis.

Fluoxetine is a selective serotonin reuptake inhibitor, which also has an immunomodulatory effect. We investigated the effects of fluoxetine and serotonin (5-HT) on the pro-inflammatory Th17- and Th1-cells in 30 patients with relapsing-remitting MS and 20 healthy subjects. Fluoxetine and 5-HT suppressed IL-17, IFN-γ and GM-CSF production by stimulated СD4+ T-cells in both groups. Blockade of 5-HT2B-receptors decreased the inhibitory effect of fluoxetine on cytokine production in MS patients. Finally, 5-HT2B-receptor activation inhibits IL-17, IFN-γ and GM-CSF production in both groups. These data suggest an anti-inflammatory role for fluoxetine in MS, which could be mediated by the activation of 5-HT2B-receptors.

Serotoninergic system targeting in multiple sclerosis: the prospective for pathogenetic therapy.

Serotonin (5-hydroxytryptamine) (5-HT) is a neurotransmitter, which mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of 5-HT on gut microbiota functions, which play an essential role in developing CNS inflammatory diseases. Finally, 5-HT is a direct mediator of neuroimmune interaction. The article reviews the literature data on the role of 5-HT in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of 5-HT and selective serotonin reuptake inhibitors (SSRIs) on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of serotoninergic drugs as a pathogenetic therapy of MS, are discussed.

The influence of glatiramer acetate on Th17-immune response in multiple sclerosis.

Glatiramer acetate (GA) is approved for the treatment of multiple sclerosis (MS). However, the mechanism of action of GA in MS is still unclear. In particular, it is not known whether GA can modulate the pro-inflammatory Th17-type immune response in MS. We investigated the effects of original GA (Copaxone®, Teva, Israel) and generic GA (Timexone®, Biocad, Russia) on Th17- and Th1-type cytokine production in vitro in 25 patients with relapsing-remitting MS and 25 healthy subjects. Both original and generic GA at concentrations 50-200 µg/ml dose-dependently inhibited interleukin-17 and interferon-γ production by anti-CD3/anti-CD28-activated peripheral blood mononuclear cells from MS patients and healthy subjects. This effect of GA was reproduced using purified CD4+ T cells, suggesting that GA can directly modulate the functions of Th17 and Th1 cells. At high concentrations (100-200 µg/ml), GA also suppressed the production of Th17-differentiation cytokines (interleukin-1ß and interleukin-6) by lipopolysaccharide (LPS)-activated dendritic cells (DCs). These GA/LPS-treated DCs induced lower interleukin-17 and interferon-γ production by autologous CD4+ T cells compared to LPS-treated DCs. These data suggest that GA can inhibit Th17-immune response and that this inhibitory effect is preferentially exercised by direct influence of GA on T cells. We also demonstrate a comparable ability of original and generic GA to modulate pro-inflammatory cytokine production.