Biology Reference
In-Depth Information
to reach their adult pattern between postnatal day 11 and 20, at a time when capac-
ity for photic entrainment of the pacemaker becomes established
[75]
. Indeed, high
doses of an IFN-/TNF- cocktail disrupt electrical activity of SCN neurons
[76,77]
.
The capacity of intracerebroventricular administration of IFN- to modify 24-hour
wheel-running activity was assessed in golden hamsters
[78]
. Animals received
IFN- or saline at ZT 6 or ZT 18. Intracerebroventricular administration of IFN-
at ZT 6 produced a significant phase advance in acrophase of rhythm, an effect not
seen with injection at ZT 18. IFN- depressed the mesor value of rhythm signifi-
cantly; the effect was seen with both ZT 6 and ZT 18 injections
[78]
. IFN- was
very effective at disrupting circadian rhythmicity of pituitary hormone release
[79]
.
These results support the view that the circadian sequels arising during the immune
reaction rely partly on central effects of IFN-
[78]
. A disruptive effect of systemic
administration of IFN- on the circadian rhythm of locomotor activity, body temper-
ature, and clock-gene mRNA expression in SCN has also been documented in mice
[80]
. Moreover, LPS incubation modified the circadian arginine-vasopressin release
from SCN cultures
[81]
. Motzkus et al.
[48]
demonstrated that IL-6 induced murine
Per1 expression in SCN cell cultures. Day/night variations of transcripts encoding
cytokine receptors and suppressors of cytokine signaling were correlated in groups
of mice of different ages, with Fos induction elicited by intracerebroventricular injec-
tions of TNF- and IFN-
[82]
. Cytokine-elicited Fos induction was high at early
night, when suppressors of cytokine signaling levels were low. Such Fos induction
was significantly reduced in the older SCN at early night, and paralleled by reduced
expression of IFN- receptor transcripts as compared to the younger SCN.
Most of the neuroendocrine effects of cytokines have been examined at single time
point in the day-night cycle, thus overlooking the intricacies of significant daily varia-
tion in pituitary hormone release. Because of this, we measured the circadian pattern
of plasma adrenocorticotropic hormone (ACTH), GH, prolactin, luteinizing hormone
(LH), and follicle-stimulating hormone (FSH) at six different time points within a
24-hour cycle in adult male Wistar rats that received five daily injections (intraperi-
toneal) of human IFN- (105 U.I./kg body weight) or saline at 08:30 hours
[79]
. A
factorial ANOVA for main effects indicated a significant (43%) increase of circulating
prolactin in IFN--treated rats. Time-of-day changes were significant for the five hor-
mones examined, and these diurnal variations became altered by IFN- administration,
with a phase-advance of the ACTH peak, a suppression of the rest-phase peak of GH,
the appearance of a second peak of prolactin at an early phase of daily photoperiod,
and blunting of the 24-hour variations of plasma FSH
[79]
. The data further pointed
to an effect of IFN- on the mechanisms responsible for the circadian organization of
pituitary hormone release. Indeed, severe immune challenges, such as animal models
of sepsis
[83]
or infection with blood-borne parasites such as
Trypanosoma cruzi
or
Trypanosoma brucei
[84]
, or HIV-infected animals or patients
[85]
display different
levels of circadian disruption, including complete arrhythmicity, suggesting that circa-
dian rhythms can be considered a good indicator of quality of health.
In recent years we have examined the circadian disruption of hormone release and
immune-related mechanisms in several animal models in which circulating cytokines
are increased, including rat adjuvant arthritis, alcoholism, calorie restriction, social
