Biology Reference
In-Depth Information
apnea. Plasma IL-1 levels also show a diurnal variation, being highest at the onset
of non-REM sleep. The levels of other cytokines (including IL-2, IL-6, IL-10, and
IL-12) and the proliferation of T cells in response to mitogens also change during
the 24-hour cycle. Although the production of macrophage-related cytokines (such
as TNF-) increases during sleep (in response to
in vitro
stimulation), this occurs
in parallel with a rise in monocyte numbers in the blood. The production of T-cell-
related cytokines (such as IL-2) increases during sleep, independent of migratory
changes in T-cell distribution
[49]
. All of these observed diurnal changes could be
specific to the effects of sleep, or could be associated with the circadian oscillator.
To dissociate the effects that result from the sleep-wake cycle from those due to the
endogenous circadian oscillator, experimental procedures such as constant routine or
forced desynchrony must be used. At present, there are no reports of studies using
these methods to elucidate the effects of sleep on immunity.
6.3 “Sickness Behavior” Includes Changes
in Circadian Rhythms
Circadian neuroimmune connections imply that the immune cells provide a very
important feedback component to the brain. Indeed, there are several mechanisms
by which the immune system can modify central clock structures
[50-53]
. In the
case of rheumatoid arthritis, inflammation is characterized by increased local syn-
ovial and systemic levels of the pro-inflammatory cytokines IL-1, IL-6, IFN-, and
TNF-, which are directly involved in the pathophysiology of this disease
[54]
: such
increased cytokine production plays a key role in neuroendocrine activation pathways
in arthritis
[55]
. As large, hydrophilic proteins, cytokines can only cross the blood-
brain barrier at leaky points (the circumventricular organs) or via specific active
transport mechanisms
[56]
. Cytokines act at the level of the organum vasculosum
laminae terminalis, a circumventricular organ located at the anterior wall of the third
ventricle. IL-1 binds to cells located on the vascular side of this circumventricular
structure, thereby inducing synthesis and release of second messenger systems, such
as nitric oxide (NO) synthase (NOS)/NO and the cyclooxygenase/prostaglandin sys-
tems
[57]
. It must be noted that a central compartment for cytokines exists and that
there are data indicating that an increase in peripheral cytokines can evoke a mirror
increase in brain levels of cytokines (for references see
[50,53]
).
Inflammatory stimuli can also induce central nervous system (CNS) stress
response through afferent peripheral neural signaling. This was shown mainly for
cytokines from the peritoneum, which can cause early rapid activation of the nucleus
tractus solitarius in the brainstem via the vagus nerve
[53,58]
. Experimental evi-
dence suggests that symptomatology after antigen administration, like anorexia and
depressed activity, is part of a defense response to antigenic challenge and is medi-
ated by the neural effects of cytokines. These changes are known generally as “sick-
ness behavior,” that is, the “nonspecific” symptoms (anorexia, depressed activity, loss
of interest in usual activities, disappearance of body care activities) that accompany
