Biology Reference
In-Depth Information
12
Cytokines, Behavior, and
Affective Disorders
Sandra V. Vellucci
Angiogenesis and TCM Laboratory, Department of Pharmacology,
University of Cambridge, Cambridge, UK
12.1 Introduction
For a long time the brain was considered an immunologically privileged site, having
a reduced responsiveness to immune challenges. Evidence for this viewpoint origi-
nated from observations that the brain lacks an adequate lymphatic system for the
capture of antigens, is protected from the general circulation by the blood-brain bar-
rier, and was thought not to exhibit the classic inflammatory response, which is char-
acterized by early invasion of macrophages and leukocytes. However, more recent
developments in the field of neuroimmunology have challenged this idea
[1]
, and it
is now established that the brain can exhibit many of the classic signs of inflamma-
tion following infection or injury. These include edema, activation of microglia, local
invasion of circulating immune cells, and cytokine production.
Before considering a possible role for cytokines in influencing behavior, one
must consider how cytokines might reach their central sites of action, particularly
as, under normal conditions, cytokines produced in the periphery cannot readily
cross the blood-brain barrier. Four different mechanisms have been proposed
[2]
.
(1) Passive transport into the brain at circumventricular sites lacking a blood-brain
barrier (e.g., the organum vasculosum of the lamina terminalis [OVLT]). (2) Binding
of cytokines to receptors in the cerebral vascular endothelium, followed by the induc-
tion of prostaglandin and nitric oxide synthesis. These, in turn, can exert a direct
influence on the brain. Cytokines may also affect the blood-brain barrier by the induc-
tion of cell adhesion molecules, such as intercellular adhesion molecule (ICAM-1)
and vascular cell adhesion molecule (VCAM-1) in the central nervous system (CNS)
endothelium, thus increasing the potential for circulating T lymphocytes, especially
CD4 T lymphocytes, to cross the blood-brain barrier. (3) Uptake into the CNS, via a
carrier-mediated, saturable transport system. Specific uptake mechanisms, for example
for interleukin (IL)-1 and IL-1, have been demonstrated at the luminal surface of
the blood-brain barrier. (4) By direct activation of peripheral (vagal) afferent terminals
following local release. For example, hepatic macrophages can release cytokines and
other pro-inflammatory mediators following challenge with bacterial lipopolysaccha-
ride (LPS), and these mediators can then activate adjacent sensory paraganglia of the
