Biology Reference
In-Depth Information
the response to infection
[59]
. These nonspecific symptoms of infection include fever
and profound psychological and behavioral changes in circadian structure
[51]
. Sick
individuals experience weakness, malaise, listlessness, and inability to concentrate
[52]
. They consistently show evidence of decreased amplitude of circadian rhythmic-
ity, like superficial sleep at night and hypersomnia, loss of interest, and depressed
activity during the day. The link between the immune system and sleep was first
identified in the 1970s, when a sleep-inducing factor was isolated and chemically
characterized from human urine: factor S, a muramyl peptide derived from bacte-
rial peptidoglycan (for references see
[60]
). Subsequently, muramyl dipeptide and
factor-S-related peptidoglycans were all shown to induce the key immunoregula-
tory cytokine IL-1. IL-1 is a potent somnogen, as well as a potent pyrogen. In fact,
IL-1 is one of the most neurologically active molecules known. Subsequent stud-
ies revealed that bacterial lipopolysaccharide (LPS), LPS components, and viral syn-
thetic dsRNA, as well as killed and living bacteria, can induce IL-1, TNF-, IL-6,
and IL-10. The presence of systemic inflammation, characterized by an elevation of
certain potent pro-inflammatory cytokines such as IL-1, IL-6, IL-10, and TNF-,
may predispose patients to develop cardiovascular complications.
In addition to acute inflammation, there is a range of other clinical conditions in
which peripheral cytokine signals might modulate brain function. Numerous stud-
ies have shown that the therapeutic administration of cytokines for the treatment of
hepatitis, cancer, multiple sclerosis, or rheumatoid arthritis induces depressive symp-
tomatology, which widely overlaps with the syndrome of sickness behavior observed
in animal models of acute inflammation
[59]
. However, during acute infection and
inflammation the amounts of circulating inflammatory cytokines are huge, usually
two orders of magnitude or more above baseline levels. In contrast, circulating levels
of cytokines are only moderately increased in the most frequent clinical situations
in which cytokines play a role in inducing symptoms of depression, such as chronic
infection or inflammation, stress, alcoholism, aging, cancer, cardiovascular disease,
or autoimmune disorders. Slightly increased TNF- and possibly also IL-6 levels are
often found in patients with these diseases
[61]
.
It is important to note that a clinically relevant immune circadian component is
the T helper 1 (Th1)/T helper 2 (Th2) balance
[62]
. Both branches support different
defense functions. Th1 responses include cell-mediated reactions that are important
for cellular pathogens, whereas Th2 responses regulate production of antibodies in
response to extracellular pathogens and mediate allergic processes. Moreover, the
effects of IFN-, a major Th1 cytokine, and IL-4, a major Th2 cytokine, are antag-
onistic. Thus, the cytokine balance, which determines the selection of the effector
mechanisms of type 1 or type 2 immunity
[62,63]
, is a factor critical for the develop-
ment of an effective immune response.
Aside from other cytokines, including IL-2 and TNF-, Th1 cells releasing mainly
INF- become activated in response to intracellular viral and bacterial challenges
and support various cellular (type 1) responses, including macrophage activation and
antigen presentation. In contrast, the cytokines typical of Th2 immunity—IL-4 as
well as IL-5, IL-10, and IL-13—tend to drive humoral (type 2) defense by stimulat-
ing mast cells, eosinophils, and B cells against extracellular pathogens. Nocturnal
