TrendsNorepinephrine: a messenger from the brain to the immune system
Section snippets
Presence and release of NE in lymphoid organs
If the nervous system is to influence immune cell function throughout the body then, ideally, NE-containing nerve fibers should be located in the immediate proximity of lymphocytes. Fulfilling this requirement, lymphoid organs contain a rich supply of sympathetic nerve fibers3 that originate in the CNS and terminate in either synaptic-like contacts or in the direct vicinity of T and B cells, permitting NE to influence lymphocyte activity directly4.
Infectious challenge, immunization with sheep
Expression of NE receptors on lymphocytes
NE modulates cellular activity by binding to adrenergic receptors expressed on various types of cells. The predominant adrenergic receptor expressed on T and B cells is the β2 adrenergic receptor9 (β2AR), a G-protein-linked receptor that classically leads to intracellular accumulation of cAMP and activation of protein kinase A upon stimulation (Fig. 2). However, recent data have revealed that β2AR stimulation activates several additional intracellular signaling mediators that are also used by
Effects on CD4+ T cells
A common dogma of the 1980s and early 1990s was that NE and β2AR stimulation suppressed lymphocyte function. However, further characterization of lymphocyte subpopulations, as well as the availability of more-sensitive techniques, has stimulated a research trend that currently challenges this. For example, recent data suggest that exposure of naive CD4+ T cells to NE may promote the IL-12-mediated differentiation of these cells into Th1 effector cells, as well as the amount of interferon γ
Effects on B cells
In addition to the ability of NE to influence B-cell function indirectly via alterations in Th1-cell cytokine production, it also directly influences B-cell function. For example, B cells produce increased levels of IgG1 and IgE when exposed to NE either during antigen processing or within the first 12 hours of culture with Th2 cells15. Interestingly, B cells produce increased levels of IgG2a only when they are exposed to NE 12 hours after culture with Th1 cells. Finally, exposure of
Clinical significance
Asthmatics commonly receive a β2AR agonist to relieve severe allergen-induced bronchoconstriction. However, agonist-induced stimulation of the β2AR expressed by lymphocytes residing in the lung may exert either a beneficial or detrimental influence on the allergic response. For example, if stimulation of the B cell β2AR by NE increases IgE production, then more mast cell degranulation may occur, thereby increasing histamine release and the intensity of the allergic response.
Another potential
Concluding remarks
We have focused here on recent work showing a role for NE and β2AR agonists in augmenting CD4+ T-cell and B-cell activity, thus challenging the commonly accepted dogma that these stimuli only suppress lymphocyte function. While the immune system is not absolutely dependent upon signals from the CNS to function, NE may either augment or inhibit lymphocyte function, resulting in either protection against, or progression of, immune-related diseases. In addition, signals from the CNS may augment
Acknowledgements
This work was supported in part by research funds from the National Institutes of Health (AI37326 and AI47420).
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