Abstract

Dopamine (DA), a neurotransmitter in the nervous system, has been shown to modulate immune function. We have previously reported that five subtypes of DA receptors, including D1R, D2R, D3R, D4R and D5R, are expressed in T lymphocytes and they are involved in regulation of T cells. However, roles of these DA receptor subtypes and their coupled signal-transduction pathway in modulation of natural killer (NK) cells still remain to be clarified. The spleen of mice was harvested and NK cells were isolated and purified by negative selection using magnetic activated cell sorting. After NK cells were incubated with various drugs for 4 h, flow cytometry measured cytotoxicity of NK cells against YAC-1 lymphoma cells. NK cells expressed the five subtypes of DA receptors at mRNA and protein levels. Activation of D1-like receptors (including D1R and D5R) with agonist SKF38393 enhanced NK cell cytotoxicity, but activation of D2-like receptors (including D2R, D3R and D4R) with agonist quinpirole attenuated NK cells. Simultaneously, SKF38393 elevated D1R and D5R expression, cAMP content, and phosphorylated cAMP-response element-binding (CREB) level in NK cells, while quinpirole reduced D3R and D4R expression, cAMP content, and phosphorylated CREB level in NK cells. These effects of SKF38393 were blocked by SCH23390, an antagonist of D1-like receptors, and quinpirole effects were abolished by haloperidol, an antagonist of D2-like receptors. In support these results, H89, an inhibitor of phosphokinase A (PKA), prevented the SKF38393-dependent enhancement of NK cells and forskolin, an activator of adenylyl cyclase (AC), counteracted the quinpirole-dependent suppression of NK cells. These findings show that DA receptor subtypes are involved in modulation of NK cells and suggest that D1-like receptors facilitate NK cells by stimulating D1R/D5R-cAMP-PKA-CREB signaling pathway and D2-like receptors suppress NK cells by inhibiting D3R/D4R-cAMP-PKA-CREB signaling pathway. The results may provide more targets of therapeutic strategy for neuroimmune diseases.

Highlights

  • Dopamine (DA), a neurotransmitter in the nervous system, has been reported to modulate immune function besides its conventional regulation of behavior, movement, endocrine, cardiovascular, renal and gastrointestinal functions

  • We have previously found that via reduction of cAMP and cAMP-response element-binding (CREB), a transcriptional factor that mediates cAMP-induced gene expression via binding to cAMP-response element in gene promoter region, D2-like receptors exert a regulatory effect on T lymphocytes, suggesting that cAMP-CREB signaling pathway is involved in modulation of T lymphocytes by DA [1]

  • To show functional significance of DA subtype receptors expressed in natural killer (NK) cells, we examined effect of D1-like receptor agonist SKF38393 on cytotoxicity of NK cells against the target

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Summary

Introduction

Dopamine (DA), a neurotransmitter in the nervous system, has been reported to modulate immune function besides its conventional regulation of behavior, movement, endocrine, cardiovascular, renal and gastrointestinal functions. We have previously shown that T lymphocytes, one population of adaptive immune cells, are modulated by DA via its receptors [1]. APO-SUS rats with a hyperdopaminergic phenotype show a decreased NK cell activity [6], and DA transporter (DAT)2/2 mice display a reduced NK cell activity [7]. These findings represent a regulation of NK cells by DA and suggest that the regulatory effect of DA on NK cells is manifold. The different regulatory effects on lymphocytes can be caused by activation of different DA receptor subtypes on these cells

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