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      Regulation of Differentiation and Function of Helper T Cells by Lymphocyte-Derived Catecholamines via α 1- and β 2-Adrenoceptors

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          Objective: Recently, we have reported that lymphocyte-derived endogenous catecholamines (CAs) facilitate a shift in the T helper (Th)1/Th2 balance towards Th2. The purpose of this study was to explore the involvement of adrenoreceptors (ARs) in Th differentiation and function modulation by lymphocyte-derived CAs. Methods: Lymphocytes were separated from the mesenteric lymph nodes of mice, stimulated with concanavalin A (Con A) and treated with pargyline, an inhibitor of CA degradation. Results: Pargyline downregulated the expression of Th1-relative factors, T-bet, interferon (IFN)-γ and interleukin (IL)-2, but upregulated the expression of Th2-relative factors, GATA-3, IL-4 and IL-10. Pargyline reduced the percentage of IFN-γ-producing CD4+ cells and the CD4+IFN-γ+/CD4+IL-4+ cell ratio, although it did not alter the proportion of IL-4-producing CD4+ cells. In addition, the percentage of CD4+CD26+ T cells and the CD4+CD26+/CD4+CD30+ cell ratio were also reduced in the pargyline-treated group. Furthermore, Con A-activated T cells treated with pargyline produced a lower level of IFN-γ and a higher level of IL-4 than the control group. All these effects were blocked by the α<sub>1</sub>-AR antagonist corynanthine or the β<sub>2</sub>-AR antagonist ICI 118551, but not by the α<sub>2</sub>-AR antagonist yohimbine or β<sub>1</sub>-AR antagonist atenolol. Conclusions: These results imply that lymphocyte-derived CAs promote polarization of differentiation and function towards Th2 cells and that this effect is mediated by α<sub>1</sub>-AR and β<sub>2</sub>-AR.

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          Most cited references 33

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          Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop.

          CD4+CD25+ regulatory T lymphocytes (Tregs) are specialized T cells playing a key role in the control of immune homeostasis. Here, we show that human Tregs constitutively express tyrosine hydroxylase (TH, EC, the rate-limiting enzyme in the synthesis of catecholamines, and contain substantial amounts of dopamine, norepinephrine, and epinephrine, which are released upon treatment with reserpine. Catecholamine release results in reduced production of interleukin-10 and transforming growth factor-beta by Tregs, and in down-regulation of Treg-dependent inhibition of effector T-lymphocyte (Teff) proliferation, which occurs without affecting the production of tumor necrosis factor-alpha or interferon-gamma. Tregs and Teffs express on the cell membrane both D1-like and D2-like dopaminergic receptors to a similar extent (12%-29% of the cells). Catecholamine-dependent down-regulation of Tregs is, however, selectively reversed by pharmacological blockade of dopaminergic D1-like receptors, which in Tregs only (and not in Teffs) are also expressed at the level of mRNA and are functionally coupled to intracellular production of cAMP. These findings indicate that in human Tregs endogenous catecholamines subserve an autocrine/paracrine loop involving dopaminergic pathways and resulting in down-regulation of Treg function.
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            Discovery of endogenous catecholamines in lymphocytes and evidence for catecholamine regulation of lymphocyte function via an autocrine loop.

            Evidence has been obtained that catecholamines and their metabolites are present in single lymphocytes and extracts of T- and B-cell clones by use of capillary electrophoresis with electrochemical detection. Pharmacological inhibition of tyrosine hydroxylase reduces observed catecholamine levels, suggesting catecholamine synthesis by lymphocytes. Intracellular dopamine levels are shown to be increased by extra-cellular dopamine, suggesting a cellular-uptake mechanism. Furthermore, incubation with either dopamine or L-dihydroxyphenylalanine, a precursor of dopamine, results in a dose-dependent inhibition of lymphocyte proliferation and differentiation. Together, these results suggest the presence of an autocrine loop whereby lymphocytes down-regulate their own activity.
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              Adrenergic modulation of immune cells: an update.

              Sympathoadrenergic pathways are crucial to the communication between the nervous system and the immune system. The present review addresses emerging issues in the adrenergic modulation of immune cells, including: the specific pattern of adrenoceptor expression on immune cells and their role and changes upon cell differentiation and activation; the production and utilization of noradrenaline and adrenaline by immune cells themselves; the dysregulation of adrenergic immune mechanisms in disease and their potential as novel therapeutic targets. A wide array of sympathoadrenergic therapeutics is currently used for non-immune indications, and could represent an attractive source of non-conventional immunomodulating agents.

                Author and article information

                S. Karger AG
                January 2015
                30 April 2014
                : 22
                : 3
                : 138-151
                Department of Physiology, School of Medicine, Nantong University, Nantong, China
                Author notes
                *Yu-Ping Peng and Yi-Hua Qiu, Department of Physiology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong 226001 (China), E-Mail yppeng@ntu.edu.cn and yhqiu@ntu.edu.cn
                360579 Neuroimmunomodulation 2015;22:138-151
                © 2014 S. Karger AG, Basel

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                Page count
                Figures: 8, Tables: 1, Pages: 14
                Original Paper


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