Biology Reference
In-Depth Information
of more specific humoral immune responses, although systemically it may suppress
Th1 responses and thus protect the organism from the detrimental effects of pro-
inflammatory cytokines and other products of activated macrophages
[39]
.
The anti-inflammatory effects of the sympathetic and parasympathetic nervous
systems seem to be synergistic in this setting. Classical teaching stresses that actions
of the sympathetic and parasympathetic nervous systems are usually in opposition,
but in many situations the two systems do function synergistically. The combined
action of these neural systems is significantly anti-inflammatory, and is positioned
anatomically to constrain local inflammation by preventing spillover of potentially
lethal toxins into the circulation through both local (neural) and systemic (humoral)
anti-inflammatory mechanisms
[29,40,41]
(
Figure 8.1
).
However, when inflammation cannot be confined locally, a transfer of cytokines
from tissue into blood may occur, generating a systemic inflammatory response syn-
drome that involves the whole organism in the inflammatory process. In this sce-
nario, cytokines may activate the inhibitory neuroimmune pathways directly, via the
bloodstream, in order to modulate and dampen the immune system and to prevent
more severe and excessive catabolic effects—including the ultimate deleterious con-
sequence, septic shock and death. Pro-inflammatory cytokines can gain access to
brain centers that are devoid of blood-brain barrier in the circumventricular region or
the area postrema. Along these lines, clinical and experimental studies suggest that
cytokines in the blood can activate the HPA axis as well as the autonomic nervous
system, and provide a shortcut by which immune recognition of an infectious chal-
lenge in the blood rapidly induces the secretion of neuroimmune modulators such
as glucocorticoids, adrenocorticotropic hormone (ACTH), -melanocyte-stimulating
hormone (MSH), catecholamines, and acetylcholine. This pathway may signal a
more severe situation compared to cytokines in tissue
[42]
.
The question is, however, what happens if the inhibitory neuroimmune pathways
are activated without a significant systemic inflammation? This can result from pro-
duction of cytokines in the brain following infection, injury, or ischemia
[41]
. The
main sources of brain cytokines are endothelial cells, invading immune cells, astro-
cytes, and microglia. These cells can produce cytokines such as IL-1, IL-6, IL-8,
IL-10, IL-12, and TNF- in response to hypoxia, endotoxin, and cell detritus
[43-48]
.
Moreover, marked increases of TNF- were localized immunocytochemically to
neurons of injured cerebral cortex. Woodroofe et al. demonstrated increased levels of
IL-1 and IL-6 in the rat brain parenchyma following mechanical injury by microdi-
alysis
[43]
. These brain-derived cytokines can directly activate inhibitory neuroim-
mune pathways and cause a brain-mediated immunodepression.
We demonstrated that sterile cerebral inflammation resulting from intra-
cerebroventricular or intra-hypothalamic infusion of rat recombinant IL-1, but not
TNF-, particularly diminished the endotoxin-induced TNF-, but increased the
IL-10 concentration in stimulated whole-blood cultures. Blocking the HPA axis by
hypophysectomy (HPX) led to complete recovery of the diminished TNF- concen-
tration and temporarily inhibited the IL-10 increase. Blocking the SNS transmission,
by application of the
2
-adrenoreceptor antagonist propranolol, not only inhibited the
increase but further down-regulated the endotoxin-induced IL-10 concentration in
