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.

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.

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.

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.

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 5152 and TNF-α release are probably D₁ receptor dependent 52.

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.

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.