Biology Reference
In-Depth Information
sleep favors a shift toward Th1-mediated immune defense. A circadian peak of the
ratio of IFN-/IL-10 production in whole blood samples is found during nocturnal
sleep. This peak was completely abolished after the administration of cortisone at
21:00 hours in the preceding evening, suggesting that the suppression of endogenous
cortisol release during early sleep plays a mediating role in the Th1 shift
[62,63]
.
However, slow-wave sleep not only suppresses the release of glucocorticoids, but
also promotes the release of growth hormone (GH) and prolactin, which support Th1
cell-mediated immunity.
In the past few years, a number of studies have started to unravel the basis for
immune-factor circadian modulation of the circadian system itself
[53]
. Several
reports indicate a possible immune feedback regulation of the circadian clock. For
example, immunosuppressant drugs such as cyclosporine affect the phase of loco-
motor activity
[64]
and of hormone secretion
[65,66]
. Moreover, immune-related
transcription factors are present and active in the SCN, and SCN activity is partially
necessary for light-induced phase shifts
[64]
.
Introduction of gram-negative bacteria into the body causes the liberation of toxic,
soluble products of the bacterial cell wall, such as LPS, also known as
endotoxin
.
Peripheral administration of LPS exerts profound effects on the sleep-wake cycle
and sleep architecture and may produce, at higher doses, fever and the characteris-
tic sickness behavior observed during inflammatory diseases, including sleep-pattern
changes and fever oscillations during the day
[60,67]
. In mice, susceptibility to lethal
doses of endotoxin increases dramatically during the resting period
[68]
, and a simi-
lar temporal pattern of induced mortality has also been established for TNF-
[69]
.
Results in hamsters indicate that LPS treatment induces changes in the phase of
locomotor activity rhythms in a manner similar to light-induced phase delays
[70]
.
The phase-shifting response to LPS was reduced when the activation of NF-B, a
transcription factor reported to play a role in the photic input of the circadian sys-
tem
[64]
, was prevented. LPS treatment stimulates the dorsal area of the SCN, as
assessed by c-Fos activation
[70]
. Astrocytes have been shown to be mediators of
immune mechanisms in several experimental models. Indeed, these cells express
cytokines and their receptors in diverse cerebral structures, as well as subunits of the
immune-related transcription (NF-B), and they respond to stimulation with LPS and
pro-inflammatory cytokines
[53]
.
Data from our laboratory indicate that melatonin, administered in the drinking
water, has the capacity to counteract the effect of LPS on body temperature in ham-
sters, when injected at “Zeitgeber” time (ZT) 0 (ZT12 defined as the time of light
off)
[71]
. Evidence that melatonin improves survival from endotoxin shock has also
been published
[72,73]
.
Therefore, one possible mechanism through which infection-related changes in
circadian rhythms can occur is by direct modification of the activity of cells in the
SCN
[53]
. Cytokine receptors (e.g., IFN- receptors) have been detected in neuronal
elements of ventrolateral SCN
[74]
. Expression of SCN IFN- receptors followed
a 24-hour rhythm, coinciding with the expression of Janus kinase 1 and 2 as well
as the signal transducer and activator of transcription factor 1, the main intracellular
signaling pathway for IFN-. In an ontogeny study, SCN IFN- receptors were found
