Endogenous catecholamine synthesis, metabolism, storage, and uptake in human peripheral blood mononuclear cells

Marino, Franca; Cosentino, Marco; Bombelli, R; Ferrari, Marco; Lecchini, Sergio; Frigo, Gianmario

doi:10.1016/s0301-472x(98)00057-5

Cited by 97 publications

(72 citation statements)

References 22 publications

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“…Thus, combining the previous data obtained with CC chemokines [16,17] with our own, one can summarize the effects of chemokines on T cell activation as follows: in activated PB T lymphocytes, Ca 2ϩ flux is activated by several CC chemokines via G i2 proteins; cell proliferation is stimulated by both CC chemokines (via G q ) and CXC chemokine IL-8 (via G i2 ); CD25 expression and IL-2 production are also stimulated by IL-8 (via G i2 ); CD69 expression seems little affected by IL-8. In addition, chemokines are far from being the only physiological autocrine/paracrine ligands of G i2 -coupled receptors in T lymphocytes: activated T lymphocytes express receptors for molecules as diverse as thrombin, opioids, cannabinoids, catecholamines, some of which are already well known as immunomodulators [14,15,39,40]. Thus, G i2 -coupled receptors and pathways represent physiological, yet underestimated, ways for human T lymphocytes to modulate their response to TCR activation.…”

Section: Discussionmentioning

confidence: 99%

Positive regulation of human T cell activation by Gi2 proteins and interleukin-8

Lippert

Jacques

Hermouet

2000

Journal of Leukocyte Biology

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We investigated whether pertussis toxin (PT)-sensitive heterotrimeric G i proteins (G i1 , G i2 , G i3 ) are involved in the regulation of TCR-induced activation of human T cells. First, G i proteins were inactivated by PT: pretreatment with PT of purified blood T lymphocytes before CD3 cross-linking inhibited cell proliferation (؊71.1 ؎ 22.0%, P F 0.001), production of interleukin-2 (IL-2; ؊47.3 ؎ 12.6%, P ‫؍‬ 0.008), and expression of CD25 (؊24.6 ؎ 11.7%, P F 0.001) and CD69 (؊25.7 ؎ 9.0%, P F 0.001). Then, to identify which of the three G i was involved, G i1 , G i2 , and G i3 proteins were specifically inactivated by stably transfecting dominant-negative mutated forms of their ␣ subunit in Jurkat cells. After activation, IL-2 production and CD69 expression were inhibited only in cells expressing inactive G i2 . We then studied the effects of interleukin-8 (IL-8), a CXC-chemokine with receptors coupled to G i2 and produced in an autocrine fashion by activated T cells. Although its effects varied among donors, exogenous IL-8 stimulated proliferation and CD25 expression (up to, respectively, 200 and 77%) of PB T lymphocytes in response to CD3 activation, in a PT-sensitive manner. IL-8 also stimulated IL-2 production (by up to 42%) and CD69 expression, although weakly (؉27%). Anti-human IL-8 antibody inhibited proliferation (؊43%) and CD25 up-regulation (؊45%) of activated T lymphocytes. In summary, several major responses of human T lymphocytes to TCRmediated activation are regulated by G i2 proteins, which for this function can be activated by IL-8 in an autocrine manner. J. Leukoc. Biol. 67: 742-748; 2000.

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Section: Discussionmentioning

confidence: 99%

Positive regulation of human T cell activation by Gi2 proteins and interleukin-8

Lippert

Jacques

Hermouet

2000

Journal of Leukocyte Biology

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“…Early sepsis is characterized by high levels of circulating catecholamines [20,60,61] that derive from the autonomous nervous system, the gut [62], lymphocytes [63,64] macrophages [65] and neutrophils [66,67]. A major mechanism of sepsis-induced cardiac dysfunction is the attenuation of the adrenergic response at the cardiomyocyte level due to down-regulation of β-adrenergic receptors [68,69] and depression of post-receptor signaling pathways [70][71][72][73].…”

Section: Underlying Mechanismsmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer

2013

CVP

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Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production. In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated. As a result, cells and organs may survive in a non-functioning hibernation-like condition. Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown. Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors. Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins. All these changes are mediated by cytokines. Treatment includes preload optimization with sufficient fluids. However, excessive volume loading is harmful. The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines. During early sepsis, cardiac output can be increased by dobutamine. While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful. Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice. While early administration of catecholamines might be necessary to restore adequate organ perfusion and pressure, prolonged administration might be harmful.Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine will reduce myocardial oxygen expenditure and ameliorate diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. However, all these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice.-3 -Alain Rudiger & Mervyn Singer: The heart in sepsis

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“…Through direct communication via sympathetic nerve fibers that innervate lymphoid organs (5), catecholamines can modulate mouse lymphocyte proliferation, differentiation, (6) and cytokine pro-duction of rodent Th cells (7) and human peripheral blood mononuclear cells (PBMCs) (8). These interactions are facilitated by adrenergic receptors expressed on murine lymphocytes (7), rat natural killer (NK) cells (9), rodent macrophages and neutrophils (10,11), and human PBMCs (12). Consequently, we need to understand better the sources, distribution, and roles of catecholamines and their receptors in immunity and inflammation.…”

Section: Introductionmentioning

confidence: 99%

“…Dopamine-transporter (DAT) mRNA, DAT immunoreactivity, and vesicular monoamine transporter immunoreactivity have been detected on cell membranes and in vesicle-like structures of human lymphocytes (37,38), suggesting DAT on lymphocytes similar to that on neurons. There is some evidence that, in addition to DATs, human PBMCs also may express a norepinephrine transporter (NAT), which would allow for active uptake of catecholamines (12). Nevertheless, the presence of NAT on immune cells remains debatable and additional confirmation is needed for definitive proof (39,40).…”

mentioning

confidence: 99%

“…Recently, both mRNA and protein for MAO and COMT were found in rat macrophages and rat neutrophils and could be induced by LPS (11). When MAO was inhibited by pargyline, the content of intracellular dopamine, norepinephrine, and epinephrine levels increased in activated human and rat lymphocytes, while intracellular catecholamine metabolites decreased (12,22). Thus, immune cells seem to possess not only the full cellular machinery for de novo synthesis, release, and inactivation of catecholamines, but also are capable of intracellular catecholamine-inactivation by MAO and COMT, utilizing the same classical metabolic pathway described in nervous and endocrine systems.…”

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confidence: 99%

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Catecholamines—Crafty Weapons in the Inflammatory Arsenal of Immune/Inflammatory Cells or Opening Pandora’s Box?

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

166

114

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It is well established that catecholamines (CAs), which regulate immune and inflammatory responses, derive from the adrenal medulla and from presynaptic neurons. Recent studies reveal that T cells also can synthesize and release catecholamines which then can regulate T cell function. We have shown recently that macrophages and neutrophils, when stimulated, can generate and release catecholamines de novo which, then, in an autocrine/paracrine manner, regulate mediator release from these phagocytes via engagement of adrenergic receptors. Moreover, regulation of catecholamine-generating enzymes as well as degrading enzymes clearly alter the inflammatory response of phagocytes, such as the release of proinflammatory mediators. Accordingly, it appears that phagocytic cells and lymphocytes may represent a major, newly recognized source of catecholamines that regulate inflammatory responses.

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Endogenous catecholamine synthesis, metabolism, storage, and uptake in human peripheral blood mononuclear cells

Cited by 97 publications

References 22 publications

Positive regulation of human T cell activation by Gi2 proteins and interleukin-8

Positive regulation of human T cell activation by Gi2 proteins and interleukin-8

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Catecholamines—Crafty Weapons in the Inflammatory Arsenal of Immune/Inflammatory Cells or Opening Pandora’s Box?

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