Biology Reference
In-Depth Information
(granzyme B and perforin), and the cytokines interferon (IFN)- and tumor necro-
sis factor (TNF)- in NK cells enriched from the rat spleen. They discovered that
the existence of molecular clock machinery is conserved across different lymphocyte
subsets and peripheral blood cells. Moreover, these cells may share common entrain-
ment signals. Emerging data in the literature suggest that circadian regulation may be
crucial for host defenses against cancer
[37,38]
.
Both the humoral arm and the delayed (cellular) arm of the immune system func-
tion in a rhythmic manner. Indeed, circadian variations in immunocompetent cells
in peripheral blood are of a significant enough magnitude to require attention in
medical diagnostics
[39,40]
. Researchers have reported circadian changes in the
circulation of T, B, or NK lymphocyte subsets in peripheral blood, and in the den-
sity of epitope molecules at their surface, which may be related to cell reactivity to
antigen exposure. Changes in lymphocyte subset populations can depend on time-
of-day-associated changes in cell proliferation in immunocompetent organs and/or
on diurnal modifications in lymphocyte release and traffic among lymphoid organs.
Circadian rhythmicity is revealed in circulating cells; lymphocyte metabolism and
transformability; circulating hormones and other substances that may exert various
actions on different targets of the immune system; cytokines, receptors, and adhesion
molecules; cell cycle events in health and cancer; reactions to antigen challenge; and
disease etiology and symptoms
[29-35,41,42]
.
It must be noted that the role of the SCN, the central circadian pacemaker, in
entrainment of lymphocyte function and in coordination of signals by which cir-
cadian information is conveyed to the immune cells, remains unsettled. Rhythms
in the number of circulating T cells persisted in rats with disrupted circadian out-
put
[43]
. Similarly, SCN ablation did not affect the 24-hour rhythms in cell cycle
phase distribution in bone marrow cells
[44]
, suggesting that some rhythms in the
immune system are SCN independent. It is known that circadian gene expression
can be maintained
in vitro
[45]
. Thus, some peripheral clocks may be able to inde-
pendently generate circadian oscillations, and this could be also the case for lym-
phocytes. Rather than a mere rhythm generator for the periphery, the SCN should
be envisioned as a transducer for light entrainment. However, there are entrainment
signals other than light that may be coordinating the rhythm in NK cell function and
other immunological parameters. For example, feeding is an important Zeitgeber for
peripheral clock-gene expression
[43]
and, interestingly enough, internal desynchro-
nization produced by restricted feeding during the light period slowed down tumor
progression in mice
[46]
. Daily activity rhythms are also considered to act as entrain-
ment cues for peripheral tissues
[47]
, and may also influence the molecular clock
in lymphocyte cells. In addition, intrinsic immunological outputs such as cytokine
secretion could function as entrainment factors for immune cells. Indeed, interleukin
(IL)-6 has been shown to induce Per1 expression
in vitro
[48]
.
Several studies have investigated the changes in cytokine levels that occur dur-
ing the 24-hour sleep-wake cycle in humans; however, it is difficult to measure
these changes because endogenous cytokine levels are low (for references see
[49]
).
Plasma TNF- levels peak during the dark phase of the cycle, and the circadian
rhythm of TNF release is disrupted by sleep pathology such as obstructive sleep
