Neurotransmitter Release by Cells of the Immune System

Lymphocytes have also been suggested to be important sites of synthesis and action of acetylcholine and catecholamines since they contain both the enzymes necessary for biosynthesis of epinephrine and acetylcholine as well as the relevant receptor system (Bergquist, Tarkowski, Ekman, and Ewing. 1994; Tayebati, El-Assouad,

Ricci, and Amenta 2002; Warthan et al. 2002). The synthesis of catecholamines was shown to increase after mitogen treatment of rat lymphocytes obtained from spleen, thymus, and mesenteric lymph nodes (Qiu, Peng, Jiang, and Wang 2004). The ability to express tyrosine hydroxylase was greatest in mesenteric lymph node cells compared to the spleen and thymus. Although more work needs to be done, the available data suggest that endogenous catecholamines may suppress IL-2 production and thereby modulate T cell expansion (Tsao, Lin, and Cheng 1998). It has been suggested that in the dual regulation of immune function by endogenous and exogenous catecholamines, endogenous catecholamines may be more important since the lymphocytes are responding to antigen and performing an immune response (Qiu et al. 2004). Similar to catecholamines, stimulating lymphocytes with mitogens enhances the synthesis and release of acetylcholine (Kawashima and Fujii 2003). Both muscarinic and/or nicotinic acetylcholine receptor agonists influence intracellular calcium levels, c-fos gene expression, nitric oxide synthesis, and IL-2 production (Fujii and Kawashima 2000; Fujino, Kitamura, Yada, Uehara, and Nomura 1997; Kawashima and Fujii 2003). Further, abnormalities in the lymphocytic cholinergic system have been detected in animal models of immune disorders (i.e., spontaneously hypertensive rat) (Fujimoto, Matsui, Fujii, and Kawashima 2001). Thus, it seems clear that immune function is, in part, under the control of nonneuronal catecholamine and cholinergic systems. The effect, if any, of lymphocyte-derived catecholamines and acetylcholine on neural activity remains to be determined. Recent work has identified a neural mechanism involving the vagus nerve and release of acetylcholine that inhibits macrophage activation termed the "cholinergic anti-inflammatory pathway" (Tracey 2002). The sensory afferent vagus pathway may be activated by low doses of endotoxin, IL-1, or products from damaged tissues. The signal is relayed to the brain where activation of the efferent vagus nerve releases acetylcholine. Acetylcholine acts to inhibit macrophage release of the proinflammatory cytokines tumor necrosis factor (TNF), IL-1 and IL-18, but not the anti-inflammatory cytokine IL-10. Thus, cholinergic neuron participation in the inhibition of acute inflammation constitutes a "hardwire" neural mechanism of modulation of the immune response. Finally, calcitonin gene-related peptide (CGRP) has also been shown to be produced and secreted by human lymphocytes and may be involved in inhibition of T-lymphocyte proliferation (Wang, Xing, Li, Hou, Guo, and Wang 2002). In another more recent study, substance P, the potent mediator of neuroimmune regulation, was shown to be up-regulated in lymphocytes by HIV infection implying it may be involved in immunopathogenesis of HIV infection and AIDS (Ho, Lai, Li, and Douglas 2002). Neuropeptides, by direct interaction with T cells, induce cytokine secretion and break the commitment to a distinct T helper phenotype (Levite 1998). Thus, neurons are not the exclusive source of neurotransmitters and, therefore, provide another instance of shared molecular signals and their receptors between the nervous and immune system.

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