Invited Minireview
The immunoregulatory role of dopamine: An update

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Abstract

The neurotransmitter dopamine (DA) is an important molecule bridging the nervous and immune systems. DA through autocrine/paracrine manner modulates the functions of immune effector cells by acting through its receptors present in these cells. DA also has unique and opposite effects on T cell functions. Although DA activates naïve or resting T cells, but it inhibits activated T cells. In addition, changes in the expression of DA receptors and their signaling pathways especially in T cells are associated with altered immune functions in disorders like schizophrenia and Parkinson’s disease. These results suggest an immunoregulatory role of DA. Therefore, targeting DA receptors and their signaling pathways in these cells by using DA receptor agonists and antagonists may be useful for the treatment of diseases where DA induced altered immunity play a pathogenic role.

Introduction

Besides conventional roles of neurotransmitters in neural communication, a large amount of evidence indicates that neurotransmitters mediate cross talk between the nervous and immune systems (Eskandari and Sternberg, 2002). Among these neurotransmitters, the role of DA is particularly interesting because in addition to regulating behavior, movement, endocrine, cardiovascular, renal and gastrointestinal functions (Basu et al., 1995, Chakroborty et al., 2008, Mezey et al., 1999, Missale et al., 1998), DA can also modulate immune functions (Basu and Dasgupta, 2000). DA is synthesized by different immune effector cells and its receptors are present in these cells (Basu et al., 1993, Basu and Dasgupta, 2000, Eldrup et al., 1989, Ferrari et al., 2004, Kirillova et al., 2008, Fur et al., 1980, McKenna et al., 2002, Nakano et al., 2008, Nakano et al., 2009). Furthermore, the sympathetic innervation of lymphoid tissues can also be dopaminergic in nature, particularly during stress (Bencsics et al., 1997, Mignini et al., 2003). As the majority of recent reports indicate unique interactions between dopamine and T cells, the main focus of this mini-review is on DA mediated regulation of T cell functions.

Section snippets

DA modulates the functions of immune effector cells by acting through its receptors present in these cells

DA is a monoamine catecholamine neurotransmitter, which acts through its D1 and D2 classes of receptors present in the target cells (Missale et al., 1998). The D1 class includes the D1 and D5 subtypes, which on activation increases intracellular cAMP (Missale et al., 1998). In contrast, the D2 class of receptors, which includes D2, D3 and D4 subtypes, inhibits intracellular cAMP on stimulation (Missale et al., 1998).

Several studies now indicate the presence of DA D1, D2, D3, D4 and D5 receptors

Altered immunity is seen in diseases with abnormal dopamine function

Altered immune functions have been observed in diseases like schizophrenia and Parkinson’s disease with abnormal dopaminergic systems (Ilani et al., 2001, Nagai et al., 1996, Wandinger et al., 1999). A significantly higher expression of DA D3 receptors and increased IFN-γ synthesis by T cells are reported in untreated schizophrenic patients (Boneberg et al., 2006, Ilani et al., 2001). On the contrary, decreased expression of DA D3 receptors and IFN-γ synthesis by peripheral lymphocytes are seen

DA regulates the functions of immune effector cells through autocrine/paracrine loop

CD4+CD25+ regulatory T lymphocytes (Tregs) are specialized T cells, which play a key role in the control of immune homeostasis (Cosentino et al., 2007). Recently, it has been demonstrated that Tregs contain substantial amounts of DA (Cosentino et al., 2007), which after being released acts on the DA D1 receptors present in these cells and subsequently suppresses IL-10 and TGF-β synthesis by these cells (Cosentino et al., 2007). In addition, the released DA by acting on DA D1 receptors

DA activates resting T cells in absence of any additional stimulating agent

Stimulation of DA D2 and D3 receptors in normal resting peripheral human T lymphocytes, activate α4β1 and α5β1 integrins in these cells, thereby promoting adhesion of these cells to the extracellular matrix component, fibronectin (Levite et al., 2001). This action of DA may be critical for trafficking and extravasation of T cells across the blood vessels and tissue barriers (Levite et al., 2001). This study is supported by Watanabe et al. (2006) who have shown that DA stimulates adhesion of CD8+

DA inhibits activation of stimulated T cells

Although DA activates resting T cells, but anti-CD3 and IL-2 induced proliferation and cytotoxicity of CD4+ and CD8+ T cells collected from normal human subjects are significantly inhibited when these cells are treated in vitro with high DA concentration observed in the plasma (48.6 pg/ml) of human subjects suffering from acute uncoping stress (Saha et al., 2001a, Saha et al., 2001b). The molecular mechanism of this action is attributed to DA D1 receptor induced increase in the intracellular

DA modulates the functions of NK cells, splenic cells, macrophages, B cells and microglial cells

There are reports which indicate that DA can also modulate the functions of other cells in the immune system (Basu and Dasgupta, 2000). Although reduced NK cell activities and ovalbumin induced delayed type hypersensitivity responses are reported in animals with hyperdopaminergic systems (Teunis et al., 2004, Kavelaars et al., 2005), but increased LPS-induced cytokine production by macrophages and ovalbumin induced humoral responses have been observed in these animals (Kavelaars et al., 2005).

Summary and conclusions

Taken together, the studies outlined above indicate that there is a well defined dopaminergic system in immunity (Basu and Dasgupta, 2000), DA is an important regulator of normal immunity (Basu and Dasgupta, 2000) and changes in the status of DA concentrations and/or receptors, especially in the T cells are responsible for abnormal immune functions seen in patients with schizophrenia and Parkinson’s disease (Ilani et al., 2001, Ilani et al., 2004, Nagai et al., 1996, Wandinger et al., 1999). It

Acknowledgments

This work was supported in parts by DRDO (LSRB/24/EPB/2001) Government of India Grant (P.S.D.); Council of Scientific and Industrial Research Government of India Fellowship9/30(43)/2005-EMR-1 to B.B., National Institutes of Health, USA Grants CA118265 (S.B.), CA124763 (S.B.) and Department of Defense Grant, USA Grant W81XWH-07-1-0051 (S.B.).

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