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Clinical review: Immunomodulatory effects of dopamine in general inflammation

Critical Care volume 8, Article number: 485 (2004) Cite this article

Abstract

Large quantitaties of inflammatory mediators are released during the course of endotoxaemia. These mediators in turn can stimulate the sympathetic nervous system (SNS) to release catecholamines, which ultimately regulate inflammation-associated impairment in tissue perfusion, myocardial impairment and vasodilatation. Treatment of sepsis is based on surgical and/or antibiotic therapy, appropriate fluid management and application of vasoactive catecholamines. With respect to the latter, discussions on the vasopressor of choice are still ongoing. Over the past decade dopamine has been considered the 'first line' vasopressor and is frequently used to improve organ perfusion and blood pressure. However, there is a growing body of evidence that dopamine has deleterious side effects; therefore, its clinical relevance seems to be more and more questionable. Nevertheless, it has not been convincingly demonstrated that other catecholamines are superior to dopamine in this respect. Apart from its haemodynamic action, dopamine can modulate immune responses by influencing the cytokine network. This leads to inhibition of expression of adhesion molecules, inhibition of cytokine and chemokine production, inhibition of neutrophil chemotaxis and disturbed T-cell proliferation. In the present review we summarize our knowledge of the immunomodulatory effects of dopamine, with an emphasis on the mechanisms by which these effects are mediated.

Introduction

The challenge to the immune system that occurs in endotoxaemia involves stimulation of immune cells to produce large amounts of inflammatory cytokines (e.g. IL-1, IL-6 and tumour necrosis factor [TNF]-α). These mediators stimulate both the hypothalamic–pituitary–adrenal axis and the systemic–adrenomedullary sympathetic nervous system (SNS). Consequently, catecholamines are released from preganglionic efferent and postganglionic SNS fibres, innervating a wide range of target organs and thereby regulating endotoxin-induced alterations in vascular resistance and tone, tissue perfusion, cardiac and renal function, and hormone release. Although dopamine is also released, noradrenaline (norepinephrine) and adrenaline (epinephrine) appear to be the principal neurotransmitters in this respect. In early and late stages of severe inflammation, catecholamine production is significantly increased [1]. Nevertheless, it must be noted that circulating catecholamines are poor markers of SNS activation during acute stress, such as occurs in sepsis [2].

Apart from their haemodynamic effects, circulating catecholamines themselves can modulate the cytokine network and thereby regulate both suppressive and stimulatory effects on immune responses. Whereas stimulation of α-adrenoreceptors is associated with induction of TNF-α or IL-1 in monocytes, β-adrenergic receptor stimulation is commonly regarded to mediate anti-inflammatory effects (i.e. inhibition of TNF-α, IL-1, IL-6 and concomitant induction of IL-10 production) [3].

Dopamine synthesis is induced rapidly under inflammatory conditions. Serum dopamine concentrations are further increased by therapeutic intervention with dopamine. The effects of low-dose treatment (i.e. up to 3 μg/kg per min) are mediated primarily via dopaminergic receptors. Their activation results in inhibition of platelet aggregation [4], induction of vasodilatation in renal, mesenteric, cerebral and coronary vessels, as well as increased systemic blood pressure and flow [5]. Therefore, over the past two decades dopamine has been considered to be and recommended as the 'first line' vasopressor [6]. Several clinical studies have now evaluated the renoprotective effect of low-dose dopamine treatment. These data indicate that dopamine may increase urine output in critically ill patients, but that is neither prevents nor improves acute renal failure [7]. Similarly, whether dopamine has beneficial effects on splanchnic blood flow is also a subject of controversy [8]. In higher concentrations (3–5 μg/kg per min), dopamine has positive inotropic effects and causes vasodilatation in the microcirculation via β1 and β2 adrenergic receptors, respectively [9]. Dopamine concentrations above 5 μg/kg per min induce platelet aggregation and α1 receptor mediated vasoconstriction, resulting in decreased microvascular blood flow [10].

It must be stressed, however, that the effect of dopamine might vary from one patient to another and depends on the state of disease [11]. Thus, in septic patients β-adrenergic effects might predominate, even at high dopamine concentrations [12]. This is attributed to different haemodynamic and cardiovascular functions, and to different tissue and body fluid distributions in these patients. Furthermore, in patients with hepatic or renal insufficiency, dopamine serum concentrations may reach even higher levels because of decreased clearance [13].

In contrast to the well recognized immunomodulatory effects of noradrenaline and adrenaline, the influence of dopamine on inflammatory responses are incompletely defined and controversially discussed. Most of our understanding of the nonhaemodynamic effects of dopamine comes from studies performed in the field of Parkinson's disease [14]. Recent studies have also indicated that treatment of kidney donors with dopamine improves long-term graft survival after kidney transplantation [15], possibly due to induction of antioxidants such as heme oxygenase 1 [16] or by reducing hypothermic preservation related transplant injury [17].

To enable a better understanding of the role of dopamine in modulating inflammatory responses, the present review summarizes the possible mechanisms of dopamine's action (Table 1).

Table 1 Immunomodulatory effects of dopamine under septic conditions
Full size table

Dopamine: mechanisms of action

Receptor mediated mechanisms

Dopamine induced immunomodulation is dose dependently mediated by different types of receptors (Table 2): the dopaminergic D1 (D1/D5) and D2 (D2/D3/D4) receptors, as well as the α and β adrenergic receptors.

Table 2 Dopaminergic receptor stimulation
Full size table

Dopaminergic receptors

Whereas D1 receptors are known to be present on smooth muscle cells, endothelial cells, platelets, lymphocytes and natural killer cells [18, 19], their presence on monocytes/ macrophages is still questioned. Stimulation of D1 receptors, as demonstrated by the use of the selective D1 antagonist SCH 23390 [20], results in activation of adenylate cyclase and subsequently generation of cAMP, which in turn activates protein kinase A (PKA) [21]. Activation of cAMP responsive element binding protein (CREB) and PKA can inhibit translocation of nuclear factor-κB (NF-κB) by retarding the degradation of the inhibitor of NF-κB, namely IκB-α [22]. Because NF-κB appears to be among the transcription factors that have been implicated in the expression of a wide range of proinflammatory genes, dopamine induced immune modulation can be explained via this pathway. NF-κB and CREB compete for the same KIX binding site on the coactivator molecule CREB-binding protein and are transcriptionally active if they are bound to CREB-binding protein only [23]. Therefore, dopamine induced CREB activation also results in diminished NF-κB dependent transcription, and hence in an impairment of the inflammatory response. Similar to D1 receptors, stimulation of D2 receptors, which are expressed on lymphocytes [24], endothelial cells [20] and platelets [19], leads to generation of cAMP and inhibits the NF-κB dependent transcription cascade. However, there are also reports indicating that stimulation of D2 receptors activates NF-κB in a time and dose dependent manner [25].

α and β Adrenergic receptors

Most inflammatory cells express α and β adrenoreceptors. Although α1 adrenoreceptor stimulation does not seem to play a role in inflammatory responses, activation of α2 receptors has a marked influence on inflammatory cells. Stimulation of α2 receptors induced the production of a variety of proinflammatory cytokines (e.g. TNF-α, IL-1 and IL-6) and antiinflammatory cytokines (e.g. IL-10). α2 Receptor mediated cytokine production is regulated via activation of protein kinase C, phosphorylation of IκB and subsequently activation of NF-κB [26].

The β-adrenergic receptors, predominantly β2, are also coupled to the cAMP–PKA pathway. Hence, stimulation of these receptors inhibits the transcription of NF-κB regulated proinflammatory genes in a manner similar to that described above [27]. Furthermore, cAMP can also indirectly activate CCAAT/enhancer binding protein [28], which, together with CREB/activating transcription factor, is believed to be largely responsible for β2 adrenoceptor mediated IL-10 production in monocytes [29].

IL-10 inhibits lipopolysaccharide (LPS) mediated TNF-α production both in vivo and in vitro [30], and it can therefore be considered part of a host protective mechanism during endotoxaemia. However, van der Poll and coworkers [31] found that in LPS-stimulated blood the increase in IL-10 levels caused by adrenaline only marginally contributed to concurrent inhibition of TNF-α production. These conclusions emphasize that the role of IL-10 as a causal factor in immunosuppression remains controversial.

Oxidative stress

Dopamine also mediates cellular effects, independent of or in conjunction with receptor activation. The clearance of dopamine depends in part on its rate of degradation by monamine oxidase (MAO)-A and MAO-B [32], which catalyzes the oxidative deamination of dopamine. Hydrogen peroxide (H2O2) is generated as a consequence of MAO mediated degradation of dopamine [33]. In the presence of Fe2+ this is further converted through the Fenton reaction into highly reactive hydroxyl radicals (HO•). H2O2 and HO• have been found to have both beneficial and deleterious effects on cells, depending on the concentration and cellular system in which they were studied. Reactive oxygen species (ROS) act as intracellular messengers activating multiple signalling pathways, including activation of c-Jun N-terminal kinase, extracellular signal regulated kinases, NF-κB and activator protein-1 [34].

Low concentrations of ROS improve the cellular redox status by increasing the amount of endogenous antioxidants such as superoxide dismutase, heme oxygenase 1 and ferritin [35]. However, as a consequence of their aggressive nature, high concentrations of ROS inevitably result in cytotoxicity and genotoxicity.

Dopamine can also form reactive metabolites through auto-oxidation. Because of the unstable nature of the catechol group, it can be oxidized to reactive quinone molecules, which themselves exert toxic effects. Although oxidation of dopamine is primarily mediated via ROS [36], a number of enzymes are able to catalyze dopamine quinone formation, including prostaglandin H synthase, xanthin oxidase and tyrosinase [37]. This auto-oxidation is prevented by antioxidants (e.g. ascorbic acid) [38]. It has been suggested that the toxicity of dopamine quinones is mediated via protein and DNA damage, ultimately leading to apoptosis [39].

Effects of dopamine on the neuroendocrine system

The production of proinflammatory cytokines and chemokines by monocytes/macrophages and endothelial cells under septic conditions is well documented. Severe inflammation is accompanied by alterations in activity of the neuroendocrine system. In the early stage of inflammation hormone release is stimulated, whereas in the late phase its release is suppressed [40]. Therefore, marked variations in serum cortisol, thyroid hormone, growth hormone and prolactin concentrations occur during the course of systemic inflammation. Dopamine suppresses the release of most if not all anterior pituitary dependent hormones [41], but at the same time it stimulates the synthesis of adrenal glucocorticoids via α2 and D2 receptors [42]. The changes induced in the hypothalamic–pituitary–adrenal axis by dopamine when it is administered in the early phase of severe inflammation are similar to those that occur in the late phase without dopamine treatment [41].

Bacterial LPS affects pituitary hormone secretion, including prolactin release, by inducing synthesis and release of cytokines such as TNF-α [43]. It is now generally accepted that prolactin can enhance monocyte, and T-cell and B-cell immune responses under normal conditions, and has beneficial effects on cell-mediated immunity after haemorrhage [44]. Because prolactin is mainly under the inhibitory control of dopamine, decreased serum prolactin concentration might lead to compromised immune function and hence susceptibility to infection [45]. Several studies have shown, that therapeutic intervention with dopamine in critically ill infants and adults dramatically decreases serum prolactin concentrations, thereby questioning the use of dopamine in these patients [46].

Effects of dopamine on the production of inflammatory mediators

Endothelial cells

The barrier function of endothelial cells is important in preventing vascular leakage and free migration of inflammatory cells. During sepsis impairment in barrier functions allows plasma proteins to enter into the interstitium, supporting oedema formation. The barrier function is further impaired by mononuclear cells, which first adhere to the endothelium and then are triggered to leave the circulation via migration between endothelial cells. D1 and D2 dopamine receptors are present on endothelial cells, rendering them responsive to dopamine. Both in vitro and in vivo studies have shown that dopamine inhibits LPS mediated upregulation of adhesion molecules expressed on macrovascular and microvascular endothelial cells [47], with a concomitant decrease in neutrophil migration [48]. Interestingly, dopamine has a dual effect on endothelial chemokine production. Although basal and LPS mediated production of growth-related-gene α (Gro-α) and epithelial neutrophil activating protein-78 (ENA-78) are significantly downregulated by dopamine, the reverse has been found for IL-8 [47]. This effect is still observed when the cells are stimulated with LPS for up to 3 hours before dopamine administration. Neither dopamineric nor adrenergic receptor antagonist were able to influence this action of dopamine. In contrast, addition of antioxidants completely prevented the action of dopamine, suggesting a pivotal role for oxidative stress. Although addition of H2O2 to microvascular endothelial cells yielded results similar to those with dopamine stimulation, neither the MAO inhibitor pargylin nor the dopamine uptake inhibitor GBR 12909 was able to inhibit the effects of dopamine.

Neutrophils

During inflammatory responses neutrophils are among the first cell types that leave the microcirculation and enter into the inflammatory site. Dopamine uptake, storage and synthesis by these cells have been described [49]. Dopamine treatment may lead either directly or indirectly to a functional suppression of neutrophils, which was demonstrated for transmigration of stimulated neutrophils after dopamine administration. This was mediated by a decreased neutrophil adhesion to endothelial cells caused by a reduction in CD11b/CD18 expression on neutrophils, and by attenuation of the chemoattractant effect of IL-8 required for transendothelial migration of neutrophils [48]. In addition, pharmacological concentrations of dopamine induce apoptosis in neutrophils isolated from healthy volunteers and reverse delayed apoptosis of neutrophils in septic patients [50]. These effects are not receptor mediated because the D1 agonist fenoldopam did not influence neutrophil behaviour. In contrast, the effects of dopamine on respiratory burst, phagocytosis [51, 52] and TNF-α release are probably D1 receptor dependent [52].

Monocytes/macrophages

It was shown that macrophages can release or store dopamine in cytoplasmic vesicles [53], but the presence of dopaminergic receptors on monocytes/macrophages has not clearly been demonstrated [54]. During the early phase of inflammation, cytokines such as TNF-α, IL-1, IL-12 p40 and IL-6, and chemokines such as IL-8 are highly upregulated in monocytes/macrophages. Dopamine or dopamine agonists significantly inhibited this [55]. In accordance with those findings, treatment with the dopamine antagonist metoclopramide stimulated constitutive and inducible expression of proinflammatory cytokines in vitro [43], whereas it suppressed chlorpromazine induced production of the anti-inflammatory cytokine IL-10 in vivo [56]. The effects of dopamine on cytokine production are mainly mediated via β adrenoceptors because the action of dopamine was partly prevented by propanolol and not influenced by dopaminergic receptor antagonists [57]. Because propanolol reversed the effect of dopamine, it has been suggested that receptor independent mechanisms might also play a role. Dopamine induced ROS are most likely involved in mediating changes in monocyte/macrophage phenotype and function [58].

Basal nitric oxide (NO) production by macrophages is not altered, or only minimally, by dopamine, whereas LPS induced NO production is strongly increased via β receptor stimulation [59]. This mechanism might contribute to the increased NO production found in critically ill patients.

Lymphocytes

Among the catecholamines, adrenaline and noradrenaline are the ones that have been most extensively investigated for their regulatory effects on immune responses in lymphocytes, antigen presenting cells and natural killer cells [60]. The synthesis and release of dopamine by lymphocytes, as well as the presence of D1 receptors, suggest regulation of functional activities such as lymphocyte proliferation, differentiation and cytokine production [61]. In vitro experiments with dopamine or the dopamine receptor agonist bromocriptine revealed a significant inhibition of lymphocyte proliferation, which was mediated either by dopaminergic receptors [62] or by ROS [63]. Furthermore, selective effects on T-cell mediated immunity (i.e. downregulation of delayed-type hypersensitivity responses) have also been described [64]. Similarly, in blood of septic patients receiving dopamine, a decrease in in vitro T-cell proliferation in response to concanavalin has been observed [46]. In contrast, in vivo experiments in mice using dopamine or D1 and D2 receptor agonists showed stimulation of basal B-cell and T-cell proliferation, and augmented LPS-induced proliferation [65]. These effects may also be indirectly mediated by influencing the microinvironment and mediator production by accessory cells [24].

Effects of dopamine on apoptosis

Dopamine is involved in the modulation of apoptosis in both neuronal and non-neuronal cells. There is evidence that dopaminergic mechanisms may contribute to neurodegeneration in Parkinson's disease. In striatal neurones high concentrations of dopamine are proapoptotic; however, low concentrations of dopamine prevent cell death, possibly due to the ability of dopamine to affect intracellular oxidative processes [66]. It is currently believed that excessive oxidant stress, induced by metabolism of dopamine, plays a major role in the pathogenesis of the selective nigrostriatal neuronal loss that occurs in Parkinson's disease. It was recently shown that dopamine, in physiological concentrations, is capable of initiating apoptosis in cultured, postmitotic sympathetic neurones. Stable transfection of Bcl-2 in PC-12 pheochromocytoma cells was able to inhibit dopamine mediated apoptosis [67]. Dopaminergic modulation of apoptosis has also been investigated in human peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. Dopamine treatment at low concentrations reduced spontaneous apoptosis, whereas apoptosis was enhanced at higher concentrations. At low dopamine concentrations this was inhibited by the D1-like receptor antagonist SCH 23390, but not by the D2-like receptor antagonists domperidone or haloperidol. At high concentrations the effect was prevented by the antioxidants glutathione or N-acetyl-L-cysteine [68]. Dopamine does not affect the expression of Cu/Zn superoxide dismutase or Bcl-2 in PBMCs. In human PBMCs, dopamine appears to promote apoptosis through oxidative mechanisms but it may also rescue cells from apoptotic death, possibly through activation of D1-like receptors. Other authors have suggested that dopamine induced apoptosis in lymphocytes is mediated by β receptors [69]. The dual effect of dopamine on human PBMCs closely resembles that on striatal neurones.

Conclusion

Because dopamine can have adverse effects on organ function during septic processes, clinical use of dopamine is increasingly being questioned. However, clinically relevant concentrations of dopamine also inhibit inflammation induced upregulation of cytokines, chemokines and adhesion molecules, and induce the production of anti-inflammatory mediators. Because of its immunomodulatory effects, dopamine might gain a new therapeutic role in the treatment of immunological dysregulation. To evaluate the immunomodulatory potential of dopamine, more clinical studies conducted in patients with or without severe inflammation would be useful.

Abbreviations

CREB:

cAMP responsive element binding protein

IL:

interleukin

LPS:

lipopolysaccharide

MAO:

monamine oxidase

NF-κB:

nuclear factor-κB

NO:

nitric oxide

PBMC:

peripheral blood mononuclear cell

PKA:

protein kinase A

ROS:

reactive oxygen species

SNS:

sympathetic nervous system

TNF:

tumour necrosis factor.

References

  1. Bergmann M, Sautner T: Immunomodulatory effects of vasoactive catecholamines. Wien Klin Wochenschr 2002, 114: 752-761.

    CAS  PubMed  Google Scholar 

  2. Pastores SM, Hasko G, Vizi ES, Kvetan V: Cytokine production and its manipulation by vasoactive drugs. New Horiz 1996, 4: 252-264.

    CAS  PubMed  Google Scholar 

  3. Barnes PJ: Beta-adrenergic receptors and their regulation. Am J Respir Crit Care Med 1999, 152: 838-860.

    Article  Google Scholar 

  4. Braunstein KM, Arji KE, Kleinfelder J, Schraibman HB, Colwell JA, Eurenius K: The effects of dopamine on human platelet aggregation in vitro . J Pharmacol Exp Ther 1977, 200: 449-475.

    CAS  PubMed  Google Scholar 

  5. McDonald RH, Goldberg LI, McNay JL, Tuttle NP: Effect of dopamine in man: augmentation of sodium excretion, glomerular filtration rate, and renal plasma flow. J Clin Invest 1964, 43: 1116-1124.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Vincent JL, de Backer D: The International sepsis forum's controversies in sepsis: my initial vasopressor agent in septic shock is dopamine rather than norepinephrine. Crit Care 2003, 7: 6-8. 10.1186/cc1851

    Article  PubMed Central  PubMed  Google Scholar 

  7. Girbes AR, Lieverse AG, Smit AJ: Lack of specific renal haemodynamic effects of different doses of dopamine after infrarenal aortic surgery. Br J Anaesth 1996, 77: 753-757.

    Article  CAS  PubMed  Google Scholar 

  8. Meier-Hellmann A, Reinhart K: Effects of catecholamines on regional perfusion and oxygenation in critically ill patients. Acta Anaesthesiol Scand Suppl 1995, 107: 239-248.

    Article  CAS  PubMed  Google Scholar 

  9. Sun D, Huang A, Mital S, Kichuk MR, Marboe CC, Addonizio LJ, Michler RE, Koller A, Hintze TH, Kaley G: Norepinephrine elicits beta-2-receptor-mediated dilatation of isolated human coronary arterioles. Circulation 2002, 106: 550-555. 10.1161/01.CIR.0000023896.70583.9F

    Article  CAS  PubMed  Google Scholar 

  10. Ahtee L, Michal F: Effects of sympathomimetic amines on rabbit platelet aggregation in vitro. Br J Pharmacol 1972, 44: 363-364.

    CAS  Google Scholar 

  11. Task Force of American College of Critical Care Medicine, Society of Critical Care Medicine: Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Crit Care Med 1999, 3: 639-660.

    Google Scholar 

  12. Cuche JL, Brochier P, Kliona N, Poirier ML: Conjugated catecholamines in human plasma: where are they coming from? J Lab Clin Med 1990, 116: 681-686.

    CAS  PubMed  Google Scholar 

  13. Le Corre P, Malledant Y, Tanguy M, Le Verge R: Steady-state pharmacokinetics of dopamine in adult patients. Crit Care Med 1993, 21: 1652-1657.

    Article  CAS  PubMed  Google Scholar 

  14. Nagatsu T, Mogi M, Ichinose H, Togari A: Changes in cytokines and neutrophils in Parkinson's disease. J Neural Transm Suppl 2000, 60: 277-290.

    PubMed  Google Scholar 

  15. Schnuelle P, Berger S, de Boer J, Persijn G, van der Woude FJ: Effects of catecholamine application to brain-dead donors on graft survival in solid organ transplantation. Transplantation 2001, 15: 544-549.

    Google Scholar 

  16. Berger SP, Hunger M, Yard BA, Schnuelle P, Van Der Woude FJ: Dopamine induces the expression of heme oxygenase-1 by human endothelial cells in vitro. Kidney Int 2000, 58: 2314-2319. 10.1046/j.1523-1755.2000.00415.x

    Article  CAS  PubMed  Google Scholar 

  17. Yard BA, Beck G, Schnülle P, Braun C, van der Woude FJ: Prevention of could preservation injury of cultured endothelial cells by catecholamines and related compounds. Am J Transplant 2003, 3: 67-78.

    Google Scholar 

  18. Santambrogio L, Lipartiti M, Bruni A, Dal Toso R: Dopamine receptors on human T- and B-lymphocytes. J Neuroimmunol 1993, 45: 113-119. 10.1016/0165-5728(93)90170-4

    Article  CAS  PubMed  Google Scholar 

  19. Emerson M, Paul W, Page CP: Regulation of platelet function by catecholamines in the cerebral vasculature of the rabbit. Br J Pharmacol 1999, 127: 1652-1656.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Basic F, Uematsu S, McCarron RM, Spatz M: Dopaminergic receptors linked to adenylate cyclase in human cerebrovascular endothelium. J Neurochem 1991, 57: 1774-1780.

    Article  Google Scholar 

  21. Platzer C, Docke W, Volk H, Prosch S: Catecholamines trigger IL-10 release in acute systemic stress reaction by direct stimulation of its promoter/enhancer activity in monocytic cells. J Neuroimmunol 2000, 105: 31-38. 10.1016/S0165-5728(00)00205-8

    Article  CAS  PubMed  Google Scholar 

  22. Neumann M, Grieshammer T, Chuvpilo S, Kneitz B, Lohoff M, Schimpl A, Franza BR Jr, Serfling E: RelA/p65 is a molecular target for the immunosuppressive action of protein kinase A. EMBO J 1995, 14: 1991-2004.

    PubMed Central  CAS  PubMed  Google Scholar 

  23. Abraham E, Arcaroli J, Shenkar R: Activation of extracellular signal-regulated kinases, NF-kappa B, and cyclic adenosine 5'-monophosphate response element-binding protein in lung neutrophils occurs by differing mechanisms after hemorrhage or endotoxemia. J Immunol 2001, 166: 522-530.

    Article  CAS  PubMed  Google Scholar 

  24. Basu S, Dasgupta PS: Dopamine, a neurotransmitter, influences the immune system. J Neuroimmunol 2000, 102: 113-124. 10.1016/S0165-5728(99)00176-9

    Article  CAS  PubMed  Google Scholar 

  25. Yang M, Zhang H, Voyno-Yasenetskaya T, Ye RD: Requirement of Gbetagamma and c-Src in D2 dopamine receptor-mediated nuclear factor-kappaB activation. Mol Pharmacol 2003, 64: 447-455. 10.1124/mol.64.2.447

    Article  CAS  PubMed  Google Scholar 

  26. Bergquist J, Ohlsson B, Tarkowski A: Nuclear factor kappa B is involved in the catecholaminergic suppression of immunocompetent cells. Ann NY Acad Sci 2000, 917: 281-289.

    Article  CAS  PubMed  Google Scholar 

  27. Farmer P, Pugin J: β-adrenergic agonists exert their 'anti-inflammatory' effects in monocytic cells through the IκB/NF-κB pathway . Am J Physiol Lung Cell Mol Physiol 2000, 279: L675-L682.

    CAS  PubMed  Google Scholar 

  28. Vogel CF, Sciullo E, Park S, Liedtke C, Trautwein C, Matsumura F: Dioxin increases C/EBPbeta transcription by activating cAMP/protein kinase A. J Biol Chem 2004, 279: 8886-8894. 10.1074/jbc.M310190200

    Article  CAS  PubMed  Google Scholar 

  29. Brenner S, Prosch S, Schenke-Layland K, Riese U, Gausmann U, Platzer C: cAMP-induced interleukin-10 promoter activation depends on CCAAT/enhancer-binding protein expression and monocytic differentiation. J Biol Chem 2003, 278: 5597-5604. 10.1074/jbc.M207448200

    Article  CAS  PubMed  Google Scholar 

  30. Inoue G: Effect of interleukin-10 (IL-10) on experimental LPS-induced acute lung injury. J Infect Chemother 2000, 6: 51-60. 10.1007/s101560050050

    Article  CAS  PubMed  Google Scholar 

  31. van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF: Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J Clin Invest 1996, 97: 713-719.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Weyler W, Hsu YP, Brakefield XO: Biochemistry and genetics of monoamine oxidase. Pharmacol Ther 1990, 47: 391-417. 10.1016/0163-7258(90)90064-9

    Article  CAS  PubMed  Google Scholar 

  33. Vindis C, Seguelas MH, Lanier S, Parini A, Cambron C: Dopamine induces ERK activation in renal epithelial cells through H 2 O 2 produced by monoamine oxidase. Kidney Int 2001, 59: 76-86. 10.1046/j.1523-1755.2001.00468.x

    Article  CAS  PubMed  Google Scholar 

  34. Chakraborti S, Chakraborti T: Oxidant-mediated activation of mitogen-activated protein kinases and nuclear transcription factors in the cardiovascular system. Cell Signal 1998, 10: 675-683. 10.1016/S0898-6568(98)00014-X

    Article  CAS  PubMed  Google Scholar 

  35. Gornekiewicz A, Sautner T, Brostjan C, Schmierer B, Fugger R, Roth E, Muhlbacher F, Bergamnn M: Catecholamines up-regulate LPS-induced IL-6 production in human microvascular endothelial cells. FASEB J 2000, 14: 1093-1100.

    Google Scholar 

  36. Nappi AJ, Vass E, Prota G, Memoli S: The effects of hydroxyl-radical attack on dopa, dopamine 6-hydroxydopa and 6-hydroxydopamine. Pigment Cell 1995, 8: 283-293.

    Article  CAS  Google Scholar 

  37. Asanuma M, Miyazaki I, Ogawa N: Dopamine- or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease. Neurotox Res 2003, 5: 165-176.

    Article  PubMed  Google Scholar 

  38. Mattamal MB, Strong R, White VE, Hsu F: Characterisation of peroxidative oxidation products of dopamine by mass spectrometry. J Chromatog B 1994, 658: 21-30.

    Article  Google Scholar 

  39. Stokes A, Hastings TG, Vrana KE: Cytotoxic and genotoxic potential of dopamine. J Neurosci Res 1999, 55: 659-665. 10.1002/(SICI)1097-4547(19990315)55:6<659::AID-JNR1>3.0.CO;2-C

    Article  CAS  PubMed  Google Scholar 

  40. Van den Berghe G, de Zegher F, Bouillon R: Clinical review: acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998, 83: 1827-1834. 10.1210/jc.83.6.1827

    CAS  PubMed  Google Scholar 

  41. Debaveye YA, van den Berghe GH: Is there still a place for dopamine in the modern intensive care unit? Anesth Analg 2004, 98: 461-468.

    Article  PubMed  Google Scholar 

  42. Bendele AM, Spathe SM, Bensllay DN, Bryant HU: Anti-inflammatory activity of pergolide, a dopamine receptor agonist. J Pharmacol Exp Ther 1991, 259: 169-175.

    CAS  PubMed  Google Scholar 

  43. Zhu XH, Zellweger R, Wichmann MW, Ayala A, Chaudry IH: Effects of prolactin and metoclopramide on macrophage cytokine gene expression in late sepsis. Cytokine 1997, 9: 437-446. 10.1006/cyto.1996.0186

    Article  CAS  PubMed  Google Scholar 

  44. Zhu XH, Zellweger R, Ayala A, Chaudry IH: Prolactin inhibits the increased cytokine gene expression in Kupffer cells following haemorrhage. Cytokine 1996, 8: 134-140. 10.1006/cyto.1996.0019

    Article  CAS  PubMed  Google Scholar 

  45. Bernton EW, Meltzer MS, Holaday JW: Suppression of macrophage activation and T-lymphocyte function in hypoprolactinemic mice. Science 1988, 239: 401-404.

    Article  CAS  PubMed  Google Scholar 

  46. Bailey AR, Burchett KR: Effect of low-dose dopamine on serum concentrations of prolactin in critically ill patients. Br J Anaesth 1997, 78: 97-99.

    Article  CAS  PubMed  Google Scholar 

  47. Beck GC, Oberacker R, Kapper S: Modulation of chemokine production in lung microvascular endothelial cells by dopamine is mediated via an oxidative mechanism. Am J Respir Cell Mol Biol 2001, 25: 636-643.

    Article  CAS  PubMed  Google Scholar 

  48. Sookhai S, Wang JH, Winter D, Power C, Kirwan W, Redmond P: Dopamine attenuates the chemoattractant effect of interleukin-8: a novel role in the systemic inflammatory response syndrome. Shock 2000, 14: 295-299.

    Article  CAS  PubMed  Google Scholar 

  49. Cosentino M, Marino F, Bombelli R: Endogenous catecholamine synthesis, metabolism, storage and uptake in human neutrophils. Life Sci 1999, 64: 975-981. 10.1016/S0024-3205(99)00023-5

    Article  CAS  PubMed  Google Scholar 

  50. Sookhai S, Wang JH, McCourt M, O'Connell D, Redmond HP: Dopamine induces neutrophil apoptosis through a dopamine D1 receptor independent mechanism. Surgery 1999, 126: 314-322. 10.1067/msy.1999.98848

    Article  CAS  PubMed  Google Scholar 

  51. Burns AM, Keogan M, Donaldson M, Brown DL, Park GR: Effects of inotropes on human leucocyte numbers, neutrophil function and lymphocyte subtypes. Br J Anaesth 1997, 78: 530-535.

    Article  CAS  PubMed  Google Scholar 

  52. Matsuoka T: Effects of dopamine on the respiratory burst in neonatal polymorphonuclear leukocytes. Pediatr Res 1990, 28: 24-27.

    Article  CAS  PubMed  Google Scholar 

  53. Marino F, Cosentino M, Bombelli R, Ferrari M, Lecchini S, Frigo G: Endogenous catecholamine synthesis, metabolism storage, and uptake in human peripheral blood mononuclear cells. Exp Hematol 1999, 27: 489-495. 10.1016/S0301-472X(98)00057-5

    Article  CAS  PubMed  Google Scholar 

  54. Morikawa K, Oseko F, Morikawa S: Immunosuppressive property of bromocriptine on human T lymphocyte function in vitro. Clin Exp Immunol 1993, 95: 200-205.

    Google Scholar 

  55. Tarazona R, Gonzalez-Garcia A, Zamzami N, Marchetti P, Ruiz-Gajo M, von Rooijen N, Martinez C, Kroemer G: Chlorpromazine amplifies macrophage-dependent IL-10 production in vivo . J Immunol 1995, 154: 861-870.

    CAS  PubMed  Google Scholar 

  56. Hasko G, Szabo C, Nemeth Z, Deitch EA: Dopamine suppresses IL-12 p40 production by LPS-stimulated macrophages via β-adrenoreceptor-mediated mechanism. J Neuroimmunol 2002, 122: 34-39. 10.1016/S0165-5728(01)00459-3

    Article  CAS  PubMed  Google Scholar 

  57. Cunha FQ, Lorenzetti BB, Poole S, Ferreira SH: Interleukin-8 as a mediator of sympathetic pain. Br J Pharmacol 1991, 104: 765-767.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Brown SW, Meyers RT, Brennan KM, Rumble JM, Narasimhachari N, Perozzi EF, Ryan JJ, Stewart JK, Fischer-Stenger K: Catecholamines in macrophage cell line. J Neuroimmunol 2003, 135: 47-55. 10.1016/S0165-5728(02)00435-6

    Article  CAS  PubMed  Google Scholar 

  59. Chi DS, Qui M, Krishnaswamy G, Li C, Stone W: Regulation of nitric oxide production from macrophages by LPS and catecholamines. Nitric Oxide 2003, 8: 127-132. 10.1016/S1089-8603(02)00148-9

    Article  CAS  PubMed  Google Scholar 

  60. Elenkov I, Chrousos GP: Stress hormones, proinflammatory and anti-inflammatory cytokines and autoimmunity. Ann NY Acad Sci 2002, 966: 290-303.

    Article  CAS  PubMed  Google Scholar 

  61. LeFur G, Phan T, Uzan A: Identification of stereospecific 3H-spiroperidol binding sites in mammalian lymphocytes. Life Sci 1980, 26: 1139-1148. 10.1016/0024-3205(80)90653-0

    Article  CAS  Google Scholar 

  62. Morikawa K, Oseko F, Morikawa S: Immunosuppressive activity of bromocriptine on human T lymphocyte function in vitro. Clin Exp Immunol 1994, 95: 514-518.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Cook-Mills JM, Cohen RL, Perlman RL, Chambers DA: Inhibition of lymphocyte activation by catecholamines: evidence for a nonclassical mechanism of catecholamine action. Immunol 1995, 85: 544-549.

    CAS  Google Scholar 

  64. Boukhris W, Kouassi E, Descotes J, Cordier G, Revillard JP: Impaired Z-dependent immune response in L-Dopa treated BALB/C mice. Clin Lab Immunol 1987, 23: 185-189.

    CAS  Google Scholar 

  65. Tsao CW, Lin YS, Cheng JT: Effects of dopamine on immune cell proliferation in mice. Life Sci 1997, 61: PL361-PL371. 10.1016/S0024-3205(97)00962-4

    Article  CAS  Google Scholar 

  66. Mladenovic A, Perovic M, Raicevic N, Kanazir S, Rakic L, Ruzdijic S: 6-Hydroxydopamine increases the level of TNFalpha and bax mRNA in the striatum and induces apoptosis of dopaminergic neurons in hemiparkinsonian rats. Brain Res 2004, 23: 237-245. 10.1016/j.brainres.2003.10.035

    Article  Google Scholar 

  67. Ziv I, Offen D, Haviv R, Stein R, Panet H, Zilkha-Falb R, Shirvan A, Barzilai A, Melamed E: The proto-oncogene Bcl-2 inhibits cellular toxicity of dopamine: possible implications for Parkinson's disease. Apoptosis 1997, 2: 149-155. 10.1023/A:1026408313758

    Article  CAS  PubMed  Google Scholar 

  68. Colombo C, Cosentino M, Marino F, Rasini E, Ossola M, Blandini F, Mangiagalli A, Samuele A, Ferrari M, Bombelli R, Lecchini S, Nappi G, Frigo G: Dopaminergic modulation of apoptosis in human peripheral blood mononuclear cells: possible relevance for Parkinson's disease. Ann N Y Acad Sci 2003, 1010: 679-682. 10.1196/annals.1299.124

    Article  CAS  PubMed  Google Scholar 

  69. Hasko G: Receptor-mediated interaction between the sympathetic nervous system and immune system in inflammation. Neurochem Res 2001, 26: 1039-1044. 10.1023/A:1012305122327

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

Thanks to the Forschungsfond of University of Mannheim for supporting the work of the authors cited in the present review.

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Authors and Affiliations

  1. Institute of Anaesthesiology, University of Mannheim, Mannheim, Germany

    Grietje Ch Beck Professor, Christine Hanusch & Jutta Schulte

  2. V Medical Clinic, University of Mannheim, Mannheim, Germany

    Paul Brinkkoetter & Benito A Yard

  3. Institute of Anaesthesiology, University of Mannheim, Mannheim, Germany

    Klaus van Ackern

  4. V Medical Clinic, University of Mannheim, Mannheim, Germany

    Fokko J van der Woude

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  1. Grietje Ch Beck Professor
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Ch Beck, G., Brinkkoetter, P., Hanusch, C. et al. Clinical review: Immunomodulatory effects of dopamine in general inflammation. Crit Care 8, 485 (2004). https://doi.org/10.1186/cc2879

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Keywords

  • adhesion molecules
  • cytokines
  • dopamine
  • hemostasis
  • sepsis

Critical Care

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