Biology Reference
In-Depth Information
5.3 Release of Norepinephrine
Electron microscopic studies of the splenic white pulp showed that sympathetic nerve
terminals were in direct apposition to T cells and adjacent to interdigitating dendritic
cells and B cells
[13,14]
. Within 9-18 hours after antigen administration to mice, NE
was released from nerve terminals in the spleen, as measured by NE turnover analy-
sis
[31]
, and was found to reach an estimated synaptic concentration of 3 10
3
M
[32]
. Upon release from the nerve terminal, NE is either metabolized by catechol-O-
methyltransferase and/or monoamine oxidase, taken back up into the nerve terminal,
lost by diffusion, or bound to a receptor on a target cell. A recent report showed that,
in addition to sympathetic nerve terminals, phagocytes may also release NE and
express the enzymes for NE synthesis and degradation
[33]
, providing another mech-
anism by which NE could be released within a microenvironment during an immune
response to modulate immune-cell activity
[34]
. Human CD4CD25 T cells were
found to express tyrosine hydroxylase and to synthesize catecholamines that may
provide an auto-inhibitory signal
[35]
. Endogenous catecholamines were found to
accelerate lymphocyte apoptosis via a mechanism that includes regulation of anti-
apoptotic and pro-apoptotic gene and protein expression, providing a mechanism for
controlling immune-cell activity
[36]
. In addition, immune-cell-derived neurotrophic
factors may direct innervating fibers to the site of the response
[37,38]
to release NE
to bind to beta-adrenergic receptors (ARs) expressed on immune-cell populations.
Thus, the initiation of an immune response in the periphery sends signals to the CNS,
resulting in subsequent regulation of the immune response via activation of the SNS
(reviewed in Ref.
[39]
).
5.4 Expression of the Beta-2-Adrenergic Receptor
Norepinephrine binds to adrenergic receptors (ARs) that are either of the alpha ()
or beta () subtype. These two subtypes of adrenergic receptors are further distin-
guished pharmacologically and biochemically as
1
,
2
, and
3
or
1
,
2
, and
3
.
Most innate immune cells, excluding natural killer (NK) cells
[40]
, are known to
express both families of adrenergic receptors. For example, bone-marrow-derived
dendritic cells express not only the
1
AR and
2
AR, but also the
1
AR and
2
AR
subtypes
[41,42]
. Likewise, monocytes/macrophages express the
2
AR subtype
[43]
, as well as the
1
AR and
2
AR
[33,44]
. In contrast, NK cells
[40]
and adaptive
immune cells express the
2
AR exclusively (reviewed in Ref.
[15]
). This dichotomy
is interesting, given that adaptive immune cells and NK cells both develop from lym-
phoid precursors in the bone marrow, as opposed to most innate immune cells, which
develop from myeloid precursors.
Radioligand binding analyses have identified the
2
ARs on both human and
murine T cells and found that, on average, CD4 T cells express approximately
200-750 binding sites per cell
[45-50]
. However, resting clones of murine Th1 cells,
but not clones of Th2 cells, express a level of
2
ARs detectable by both radioligand
