Invited MinireviewThe immunoregulatory role of dopamine: An update
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.).
References (45)
- et al.
Identification of dopamine plasma membrane and vesicular transporters in human peripheral blood lymphocytes
J. Neuroimmunol.
(2001) - et al.
Dopamine, a neurotransmitter, influences the immune system
J. Neuroimmunol.
(2000) - et al.
Uptake and biodistribution of dopamine in bone marrow, spleen and lymph nodes of normal and tumor bearing mice
Life Sci.
(1993) - et al.
Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNF alpha or both
J. Neuroimmunol.
(2005) - et al.
D3 dopamine receptor mRNA is elevated in T cells of schizophrenic patients whereas D4 dopamine receptor mRNA is reduced in CD4+-T cells
J. Neuroimmunol.
(2006) - et al.
In vivo administration of l-dopa or dopamine decreases the number of splenic IFN gamma-producing cells
J. Neuroimmunol.
(2003) - et al.
Catecholamines inhibit microglial nitric oxide production
Brain Res. Bull.
(2000) - et al.
Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop
Blood
(2007) - et al.
Dopamine and noradrenaline control distinct functions in rodent microglial cells
Mol. Cell Neurosci.
(2005) - et al.
Dopaminergic D1-like receptor-dependent inhibition of tyrosine hydroxylase mRNA expression and catecholamine production in human lymphocytes
Biochem. Pharmacol.
(2004)