Biology Reference
In-Depth Information
lymphoid organ exists, the
2
AR is expressed on the surface of immune cells, and
immune cells are exposed to a AR agonist, the level of intracellular cAMP and pro-
tein kinase A (PKA) activity increases. The following sections present the findings
that have identified the changes induced in immune-cell activity following
2
AR
stimulation and a change in cAMP and PKA activation, as well as the mechanisms
by which these signaling intermediates affect gene expression and immune-cell
function.
5.5 Evidence That Norepinephrine Regulates
Immune-Cell Function
The innate immune system protects in an antigen-nonspecific manner and does not
generate memory cells. In contrast, the adaptive immune system protects in an anti-
gen-specific manner and generates long-term protection in the form of memory cells.
Pharmacological evidence shows that the SNS is involved in regulating the level of
response in both the innate and adaptive immune systems. Early studies used the
chemical neurotoxin 6-hydroxydopamine (6-OHDA) to reversibly deplete NE from
peripheral sympathetic nerve terminals in adult mice. Depending on the model sys-
tem and antigen used, such NE-depleted mice had either enhanced, suppressed, or
unaltered immune responses when compared to mice in which NE remained intact
(reviewed by Ref.
[65]
), suggesting that NE released from nerve terminals within the
microenvironment of immune cells regulated the response to antigen. These data set
the stage for many studies designed to determine the mechanisms by which NE and
2
AR engagement on the cell surface of various immune cells affecting these cells'
activity. The subsequent sections summarize these findings.
5.6 NK Cells
Natural killer cells
are innate immune cells that mediate killing of microbe-infected
cells by lysis and production of interferon-gamma (IFN-). Acute stress or the infu-
sion of an adrenergic agonist has been reported to cause a rapid and transient increase
in the number of circulating NK cells
[66-71]
that is prevented completely by admin-
istration of a
2
AR antagonist
[67,70,71]
. There is evidence from an
in vitro
study
that NK cell adherence to cultured vascular endothelium is inhibited in the presence
of a
2
AR agonist
[72]
, and that NK cell activity is reduced
[73-76]
. Likewise, NE
reduces the ability of NK cells to bind to a target cell, and the mechanism appears to
involve a reduction in CD16 expression on NK cells
[76]
. In addition, NE inhibited
NK cell release of IFN- and tumor necrosis factor-alpha (TNF-), and this effect
prevented NK cell maturation into a functional cytotoxic cell
[76]
. Thus, the effect
of NE and
2
AR stimulation on NK cell number and activity appears to be primarily
inhibitory.
