Dopamine in Immunoregulation

In this issue Toth et al. [1] discusses the role of peripheral and brain derived dopamine (DA) in immune regulation. Here we consider briefly the possible way by which hormones and other central regulatory factors act peripherally in vivo. During the early years of the nineteenth centaury Endocrinologists recognized first when searching for the origin of hormones, that “everything is made everywhere”. This rule was true for all hormones and neurotransmitters that have been examined. This phenomenon has been re-discovered since that time over and over again. DA exerts an inhibitory effect on prolactin (PRL) and growth hormone (GH) secretion. This effect is very powerful. In rats treatment with bromocriptine (a DA agonist drug), inhibited completely the adaptive immune function (ADIM) [2]. The rule in the Neuroimmune Supersystem [3] is that mediators are shared: so classical hormones and neuropeptides are made in the immune system and everywhere else, lymphokines were discovered in the immune system first, but then were found in many other tissues and cells so their name was changed to cytokines, which implies tissue hormones. Sharing makes communication instantaneously possible [3]. Dopamine is no exception to this rule. It is made in the central nervous system (CNS) but also in various cell types in the immune system, and in many other tissue and organs in the body. In short, dopamine is made everywhere and acts everywhere [1]. One may argue that dopamine is a powerful immunoregulator, it can act centrally by inhibiting PRL secretion, and also acts peripherally by paracrine/autocrine (P/A) regulation. Yes indeed, this is very important from the point of usefulness. But how the central and peripheral mechanisms work under homeostatic conditions? There are myriads of mediators produced centrally, peripherally, and receptors are expressed and may be activated everywhere. This may lead to a very chaotic situation, signals are delivered everywhere; cells could go crazy under such bombarding. It was proposed that membrane bound receptors will cap on one pole of the cell surface after activation by specific ligands. Such receptors are phosphorylated by protein kinases and de-phoshorylated by phosphatases, which happens competitively at the same time. If phosphorylation is stronger the cell will be activated, if de-phosphorylation is stronger, the cells will be inhibited [4]. But there are many other mediators that do not use this signal transmission pathway. Alternate mechanisms are used by some membrane receptors. Also, there are cytoplasmic and nuclear receptors, which definitely would not be controlled by this kind of regulation [5]. It is important that every regulatory circuit has positive and negative signals and the signals will balance out physiologically, possibly under CNS control. The fact is that in spite of the countless mediators, receptors and signaling, the organism remains normal, all functions are in harmony and in homeostasis. The classical answer is that the CNS controls everything, so the peripheral mechanisms are kept under control by the CNS. Indeed we observed that PRL production by lymphocytes was regulated by the pituitary gland [6]. This would suggest that the CNS might exert a regulatory influence on all regulatory circuits under normal, homeostatic conditions. Could DA of CNS origin signal the immune system or other systems, tissues directly? The answer is yes. Dopaminergic nerves deliver DA to the tissues for local use. Apparently the CNS is in control here again. So it seems that during homeostasis, the local consumption of DA may be CNS regulated [1]. During homeostasis, cytokines are at minimal or undetectable level in the serum. During acute febrile illness cytokines of innate immunity (INIM) origin [e.g. interleukin – (IL1)-beta, IL-6, and tumor