Regulation of Cytokine Balance by Monoamines in Healthy and in Depressed States

The major source of cytokine production is the peripheral immune system, although cytokines are also produced in the CNS. It is now well established that immune activation triggers the sympathetic nervous system (SNS) to release its neurotransmitters NE, epinephrine, and dopamine (Besedovsky, del Rey, Sorkin, and Dinarello 1986; Akiyoshi, Shimizu, and Saito 1990; Shimizu, Hori, and Nakane 1994).

The sympathetic nervous system innervates immune organs and, when activated, releases its signaling molecules in the vicinity of immune cells. Accordingly, cytokine balance can be modulated by sympathetic neurotransmitters both in the CNS and in the periphery. Immune cells express various neurotransmitter receptors that are sensitive to monoamines, and the production of cytokines (and other immune/inflammatory mediators (chemokines and free radicals) is modulated by activation of these receptors (Elenkov et al. 2000).

Once the neurotransmitters have reached the target cells, they occupy their appropriate receptors and the initiated signal transduction modulates the cytokine production in the cell. There is ample evidence that in this modulatory effect, cAMP plays one of the key roles (Bourne, Lichtenstein, Melmon, Henney, Weinstein, and Shearer 1974; Kambayashi, Jacob, Zhou, Mazurek, Fong, and Strassmann 1995; Vizi 1998). Thus, occupation of neurotransmitter receptors that stimulate/or inhibit adenylate-cyclase influences the cytokine profile of the system. NE and adrenergic drugs may influence the immune response directly, through the adrenergic receptors expressed on macrophages and also on other immunologically competent cells, as well as indirectly via alteration of the endogenous NE level by influencing the activity of release-regulating presynaptic a2-adrenoceptors (a2-AR) located on sympathetic nerve terminals (Elenkov and Vizi 1991; Vizi 1998; Szelenyi et al. 2000b; Szelenyi, Kiss, and Vizi 2000a). Activation of the presynaptic a2-adrenoceptors results in a negative feed back effect on NE release, leading to decreased extracellular NE concentration (Vizi 1979; Kiss et al. 1995). The majority of the direct effect of NE is prevailed via the p2-adrenoceptors expressed by various immune cells (Hasko, Szabo, Nemeth, Salzman, and Vizi 1998a; Szelenyi et al. 2000a).

The effect of catecholamines and adrenergic drugs in inflammation and sepsis is one of the most thoroughly studied examples of neuroimmunomodulation. Adrenoceptors are known to be coupled to various G-proteins, either stimulating (Gs) or inhibiting (Gi) adenylate-cyclase, and there is evidence that among the three major adrenoceptor groups (a1-, a2-, and the P-adrenoceptor subtypes, i.e., P1-, P2-, and p3-adrenoceptors), at least a2-, P1-, and p2-adrenoceptors play major roles in the regulation of cytokine balance.

Several groups demonstrated that the activation of p2-adrenoceptor on macrophages resulted in suppression of the LPS-induced proinflammatory cytokine production (Hasko, Szabo, Nemeth, Salzman, and Vizi 1998b; Izeboud, Mocking, Monshouwer, van Miert, and Witkamp 1999; Elenkov et al. 2000; Szelenyi, Kiss, Puskas, Selmeczy, Szelenyi, and Vizi 2000c). Stimulation of p2-adrenoceptor is the classical example of activation of adenylyl cyclase via stimulatory G protein (Gs)

resulting in the subsequent increase in intracellular cAMP. Since cAMP is generally proved to suppress the inflammatory immune response, i.e., the sympathetic activation, it inhibits the innate immune response (van der Poll, Jansen, Endert, Sauerwein, and van Deventer 1994; Elenkov et al. 2000; Chong, Shin, and Suh 2003). Recently, however, evidence was given that the modulatory effect of P2-adrenoceptor on the proinflammatory/antiinflammatory cytokine balance was not necessarily immunosuppressive but just the opposite depending on the applied stimulus. However, the exact molecular mechanisms have not yet been fully understood (Szelenyi, Selmeczy, Brozik, Medgyesi, and Magocsi 2006).

As both a2- and p2-adrenoceptors are expressed on the surface of various immune cells (Abrass, O'Connor, Scarpace, and Abrass 1985; Spengler, Allen, Remick, Strieter, and Kunkel 1990), they can exert a direct regulatory effect on cytokine production via modulation of the cAMP level in the cell. This means that ligand binding of a2-adrenoceptors decreases while activation of P-adrenoceptors increases the cAMP level in the cell, resulting in an increasing effect of proinflammatory cytokine production for a2-, and in an opposite effect in the case of P-adrenoceptors.

Macrophagic a2-adrenoceptors have only a minor role, although, there is evidence that it also may have a substantial modulatory role in cytokine production both in vitro and in vivo. Occupation of a2-adrenoceptors on macrophages results in the suppression of intracellular cAMP levels because these receptors are associated with a Gi-type protein (Bylund et al. 1994). Since there is a negative correlation between cAMP levels and inflammatory cytokine production in macrophages (van der Pouw Kraan, Boeije, Smeenk, Wijdenes, and Aarden 1995; Nemeth, Hasko, Szabo, and Vizi 1997; Hasko et al. 1998b) the decreased levels of cAMP may explain the increased TNF-a production. Generally, those catecholamine receptors that upon activation increase the accumulation of cAMP were shown to reduce the synthesis of TNF-a (Katakami, Nakao, Koizumi, Katakami, Ogawa, and Fujita 1988; Elenkov, Hasko, Kovacs, and Vizi 1995), IL-2 (Novogrodsky, Patya, Rubin, and Stenzel 1983), IFNy (Ivashkiv, Ayres, and Glimcher 1994), and IL-12 (van der Pouw Kraan et al. 1995), while the increase in cAMP levels stimulates IL-4 (Lacour, Arrighi, Muller, Carlberg, Saurat, and Hauser 1994), IL-5 (Siegel, Zhang, Ray, and Ray 1995), IL-6 (Surprenant, Rassendren, Kawashima, North, and Buell 1996), and IL-10 (Platzer, Meisel, Vogt, Platzer, and Volk 1995). Thus, activation of neurotransmitter receptors that stimulate adenylate-cyclase leads to a shift toward T helper 2 (Th2)-type responses being anti-inflammatory and protective, whereas downregulation of intracellular cAMP stimulates a T helper 1 (Th1)-type response, resulting in inflammatory and cell-destructive effects.

Consistent with pathophysiology of depression, it was demonstrated that proinflammatory cytokine-induced behavioral changes were associated with alterations in the metabolism of monoamine neurotransmitters; serotonin, norepinephrine, and dopamine. Changes in catecholamine metabolism in brain regions being essential to the regulation of emotion including the limbic system (amygdala, hippocampus, and nucleus accumbens), might influence sickness behavior (Dunn, Wang, and Ando 1999; Gao, Jiang, Wilson, Zhang, Hong, and Liu 2002). In addition to the effects on neurotransmitter metabolism, inflammatory cytokines exert profound stimulatory effects on the HPA axis hormones as well as on

CRH (mRNA and protein), both in the hypothalamus and in the amygdala, a brain region that has an important role in fear and anxiety (Besedovsky and del Rey 1996; Capuron and Miller 2004). These effects are, in large part, mediated by the cross talk of cytokines and their receptors within the HPA axis tissues that facilitate the integration of cytokine signals (Silverman, Pearce, Biron, and Miller 2005). The cytokine signal transduction pathways that include mitogen-activated protein kinases (MAPKs) (Kaminska 2005; Szelenyi et al. 2006) and NF-kB, are also able to disrupt glucocorticoid receptor signaling (Wang, Wu, and Miller 2004), and thus might contribute to altered glucocorticoid-mediated feedback regulation of both CRH and of further proinflammatory cytokine release. In addition, activation of p38 MAPKs might contribute to disturbances in neurotransmitter function through effects on the serotonin transporter (Zhu, Carneiro, Dostmann, Hewlett, and Blakely 2005).

The first monoamine hypothesis of depression was based on the observation that depression was associated with a decrease in noradrenergic neurotransmission (Schildkraut 1965) accompanied with supersensitivity of the inhibitory, presynaptic a2-ARs leading to postsynaptic P-adrenoreceptor up-regulation. This was first of all based on the observed antidepressant effect of the monoamine transporter inhibitors that increase the biophase level of the monoamine in question. In the meantime, however, a number of studies have found significantly higher plasma, urine, and cerebrospinal fluid (CSF) NE levels in patients with depression than in controls (Potter et al. 1985; Maes, Minner, Suy, Vandervorst, and Raus 1991). Consequently, this catecholamine-depletion hypothesis has become strongly disputed. Considering the complexity of the phenomenon, a "dysregulation hypothesis" was proposed, in other words, an impaired negative feedback on the presynaptic neuron might cause increased/decreased NE release. Evidence was also described for a subsensitivity instead of supersensitivity of the presynaptic a2-ARs (Kafka and Paul 1986; Maes, Van Gastel, Delmeire, and Meltzer 1999a). This subsensitivity of the central a2-ARs may be the cause of an impaired negative feedback on the presynaptic catecholaminergic neuron, which in turn may induce the loss of inhibition to external stimuli of noradrenergic output in response to any activation. In contrast, in animal depression models (see later) the enhancing effect of a2-AR antagonist on the endogenous release of NE could be demonstrated, suggesting that the negative regulatory a2-ARs were not desensitized (Vizi, Zsilla, Caron, and Kiss 2004; Gilsbach et al. 2006). Thus, dysregulation of the NE system may also contribute to the pathophysiology of depression (Maes et al. 1999b), while a number of other theories are also trying to understand the background of this heterogeneous disorder.

Effects of cytokines on the noradrenergic system have also been described. IL-1 was shown to stimulate hypothalamic and preoptic noradrenergic neurotransmission (Dunn 1988), similar to the effects observed after administration of various forms of IL-1 (Dunn et al. 1999). There are inconsistent data for other proinflammatory cytokines on their influence on noradrenergic neurotransmission. IL-2 showed similar effects as IL-1, while other studies reported that TNF-a inhibited NE release from the median eminence (Elenkov, Kovacs, Duda, Stark, and Vizi 1992).

The immunomodulatory effects of dopamine (DA) are not as definite and well studied as those of NE. It should be emphasized that, as for NE, the nature of the immunomodulatory effect of DA is determined by the type/subtype of the receptor occupied by it. For example, it has been shown that the suppressive action of DA on

IL-12 production in cultured macrophages prevails partly through p2-adrenoceptors (Hasko, Szabo, Nemeth, and Deitch 2002), whereas a role for dopamine D2 receptors has been suggested for the observed in vivo suppression of interferon-y (IFN-y) and TNF-a (Sternberg, Wedner, Leung, and Parker 1987; Ritchie, Ashby, Knight, and Judd 1996).

Disturbances in the serotonergic neurotransmission also play a causal role in the pathophysiology of depression. Several neurochemical changes in the 5-HT system are found in depressed people. Tryptophan (Trp), the precursor of 5-HT, has to compete with other competing amino acids and certain changes in 5-HT metabolism have been shown. The effect of 5HT is also dependent on the type/subtype of the receptors involved in its action. 5-HTT is located on the presynaptic membrane whereas 5-HT is located in cell bodies in the raphe nuclei (RN) where it regulates 5-HT levels in the synaptic cleft by modulating the reuptake of 5-HT into the presynaptic cell (Staley, Malison, and Innis 1998). Other central changes of the 5-HT system in depression include changes in 5-HT2 and 5-HT1A brain receptors (Lesch and Mossner 1998).

Concerning the serotonergic system, cytokines have substantial effects on its function in the brain and in the periphery. Peripheral and central administration of IL-1P, IFN-y, and TNF-a significantly increase extracellular serotonin (5-hydroxy-triptamine, 5-HT) concentrations in several brain areas of rats (Clement et al. 1997).

Cytokines, such as IL-1, IFN-y, and TNF-a were shown to stimulate 5-HT neurotransmission and to reduce the production of 5-HT (Heyes et al. 1992). These proinflammatory cytokines have also been shown to up-regulate the 5-HTT, causing a depletion in extracellular 5-HT (Morikawa, Sakai, Obara, and Saito 1998; Mossner, Heils, Stober, Okladnova, Daniel, and Lesch, 1998). No changes were found after IL-6 injection. Among the anti-inflammatory cytokines, IL-4 was shown to induce a reduction in 5-HT uptake (Mossner, Daniel, Schmitt, Albert, and Lesch 2001).

Finally, we should emphasize that the monoamine theory of depression is only one, oversimplified version of the known possibilities, although its importance in the therapy of depression is not questionable and the regulatory role of the extracellular monoamine level both on sleep and on inflammatory immune response is of great importance.

Nevertheless, it is beyond the scope of this chapter, and depression is known to be a pleiotropic entity with a very complex background that should be studied in its whole diversity.

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