Elsevier

Biochemical Pharmacology

Volume 56, Issue 9, 1 November 1998, Pages 1079-1087
Biochemical Pharmacology

Commentaries
Regulation of cytokine and chemokine production by transmitters and co-transmitters of the autonomic nervous system

https://doi.org/10.1016/S0006-2952(98)00153-1Get rights and content

Abstract

The sympathetic nervous system innervates immune organs and, when activated, releases its signaling molecules in the vicinity of immune cells. The released molecules include the “classical” transmitters norepinephrine and epinephrine and the co-transmitters ATP and adenosine. Immune cells express various adrenergic and purinergic receptors that are sensitive to these molecules, and the production of immune/inflammatory mediators (cytokines, chemokines, and free radicals) is modulated by activation of these receptors. Notably, the production of tumor necrosis factor-α, interleukin-6, -10, and -12, and the chemokine macrophage inflammatory protein 1α and the production of the free radical nitric oxide, produced by the inducible nitric oxide synthase, have been shown to be altered by activation of these receptors. Alterations in the production of the immune mediators may contribute to the development of various diseases. On the other hand, novel experimental therapies based on the modulation of adrenergic or purinergic receptors on immune cells are emerging. Such approaches may have beneficial effects in limiting tissue injury and suppressing symptoms in certain pathophysiological states.

Section snippets

Release of transmitters of the sympathetic nervous system in the vicinity of immune cells

The autonomic nervous system consists of two major components that originate in the CNS: the sympathetic and parasympathetic division. The sympathetic division sets out from nuclei within the brainstem and gives rise to preganglionic efferent fibers that terminate in the paravertebral or prevertebral ganglia. The postganglionic noradrenergic fibers innervate a wide variety of target organs including the heart, gastrointestinal tract, blood vessels, and lymphoid organs. These fibers give rise to

Role of adrenergic receptors in the modulation of cytokine, chemokine, and free radical production

The catecholamines NE and EPI exert their effects by binding to 7 transmembrane spanning G-protein-coupled cell surface receptors termed adrenoceptors. Adrenoceptors can be classified into three major groups: α1-, α2-, and β-adrenoceptor types. Each of these three major types can be subdivided further into at least three subtypes: α1A, α1B, α1C; α2A, α2B, α2C; and β1, β2, and β3.

Regulation of cytokine and no production by purinoreceptors

Immune cells express plasma membrane receptors for extracellular ATP and ADO. Receptors for ATP are termed P2 purinoceptors, while ADO-sensitive receptors are called P1 or ADO receptors. Both ATP and ADO can be present at physiologically relevant concentrations in the vicinity of immune cells 74, 75, 76 and can exert their effects at various subtypes of purinoceptors. ATP receptors are classified as metabotropic (G-protein-coupled) P2y or ionotropic (ion channel) P2x receptors. ADO interacts

Endotoxic shock

The management of severe sepsis includes the administration of ligands of both α- and β-adrenoceptors, aiming to provide cardiovascular support. Such support includes the administration of α-adrenergic agonists to maintain perfusion pressure, and the use of β-adrenergic agonists to improve cardiac output. As discussed above, accumulating evidence shows that these agents can affect the production of inflammatory mediators, which are responsible for the deleterious effects of shock-inducing

Conclusions

Immune cells express various adrenergic and purinergic receptors that are sensitive to transmitters of the SNS. The production of immune/inflammatory mediators (cytokines, chemokines, and free radicals) is modulated by activation of these receptors. The investigations are only at the initial stages of exploring the complex regulation of the production of pro- and anti-inflammatory mediators by various receptor subtypes of the adrenergic and purinergic receptors. Continuing work in this area is

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    Corresponding author: Dr. Csaba Szabó, Children’s Hospital Medical Center, Division of Critical Care, 3333 Burnet Ave., Cincinnati, OH 45229 [Tel. (513) 636-8714; FAX (513) 636-4892].

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