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Johannes-Müller-Institut für Physiologie, Medizinische Fakultät Charité, Humboldt-Universität Berlin, 10117 Berlin, Germany
IMAGINE
YOU WERE HIT BY THE FLU. Taking a look at the American
Journal of Physiology-Regulatory, Integrative and Comparative Physiology in this unpleasant situation will certainly not prevent you from getting a fever. However, by doing so you can learn at least
some interesting news about the mechanisms that control your body temperature.
Bacterial lipopolysaccharides (LPS) induce fever that is mediated by
pyrogenic cytokines, such as IL-1 There are also "good" cytokines that may counteract an increase of
the body core temperature. For example, the febrile response induced by
IL-1 In addition to enhanced cytokine release, the PGE2 system
is another important downstream mediator of fever and inflammation. Recent experimental evidence indicates that activation of
PGE2 by bacterial LPS involves both differential
transcriptional upregulation of PGE2 synthesizing enzymes
(12) and downregulation of PGE2 carriers and
catabolizing enzymes in various tissues (14). Among the
most remarkable changes in LPS-injected rats was a decrease in the
expression of hepatic and pulmonary 15-hydroxy-PG-dehydrogenase and
increased microsomal PGE synthase as well as secretory phospholipase A2-II-A mRNA in the hypothalamus and liver
(14). These enzymes are therefore attractive targets for
anti-inflammatory therapy. It seems that the PGE2 pathway
is also responsible for the attenuation of fever in pregnant animals.
Thus LPS-induced PGE2 production was suppressed in the
brain of near-term pregnant rats, and this effect was correlated with
blunted cyclooxygenase-2 induction in brain endothelial cells of these
animals (11, 19). The sensitivity to PGE2 was
also maintained during hibernation as demonstrated by the finding that
intracerebrovascular infusion of PGE2 in golden-mantled
ground squirrels provoked arousal from hibernation and induced fever
(21). It is believed that periodic arousals may activate a
dormant immune system, which can then combat pathogens that may have
been introduced immediately before or during hibernation
(21).
The central heme oxygenase (HO) pathway was reported to play an
important role in the genesis of LPS-induced fever. Novel findings
suggest that among the HO products involved, i.e., biliverdine, free
iron, or carbon monoxide, CO acting via a soluble guanylate cyclase is
the most likely candidate for LPS fever. This conclusion is based on
the findings that intracerebroventricular application of biliverdine or
iron salts as well as treatment with the iron chelator deferoxamine
elicited no change in basal body core temperature (23).
However, heme-induced pyresis was completely prevented by inhibition of
the soluble guanylate cyclase pathway, which is normally
activated by CO (23). In an effort to study the role of
the nitric oxide (NO) system in the regulation of body core
temperature, the NO synthase inhibitor
NG-monomethyl-L-arginine
(L-NMMA) was injected into the anteroventral preoptic
region (AVPO) of rats. L-NMMA did not affect the basal body
core temperature but enhanced the early stage of LPS fever, indicating
that NO plays an antipyretic role in the AVPO (22). It
seems that peripherally generated NO contributes to the genesis of
fever, whereas brain NO may act as an endogenous antipyretic factor, at
least in response to systemic inflammation (22).
The role of the liver in modulating the fever response to pyrogenic
stimuli is highlighted in two studies, which appeared in the
American Journal of Physiology-Regulatory, Integrative and
Comparative Physiology. One of these studies shows that selective inhibition of hepatic protein synthesis with
D-galactosamine (D-gal) blunted the febrile
response to LPS in both control animals and heat-conditioned rats
(2). Intraperitoneal injection of D-gal also
abolished pyrogenic tolerance to repeated treatment with muramyl
dipeptide, suggesting that hepatic function may be important not only
for the development of tolerance to endotoxin (20) but
also to other pyrogenic stimuli (3). Although muramyl
peptide and LPS are T cell-independent stimuli of the immune system,
the staphylococcal enterotoxin B was used to assess the role of the T
cell system in eliciting an immune response. Intraperitoneal injection
of staphylococcal enterotoxin B resulted in a significant rise of body
temperature in rats and elevation of plasma corticosterone as well as
c-Fos expression in parvocellular neurons within the paraventricular
nucleus of the hypothalamus (6). These observations support the idea that T cell-dependent immune stimuli activate brain
pathways mediating host-defense responses such as fever and
neuroendocrine changes (6).
As outlined in several contributions, the fever response to pyrogenic
signals is not uniform but depends on various external and endogenous
conditions. For example, alcohol consumption was reported to aggravate
alterations in body temperature due to shift work, jet lag, and aging
in humans (1). Furthermore, rats suffering from repeated
restraint (9) or physical stress (15) showed enhanced response to LPS both in terms of body core temperature as well
as hypothalamic-pituitary-adrenal function. Another interesting aspect
refers to the fact that LPS-induced fever is related to behavioral
thermoregulation in young and old rats. For example, young rats that
were injected with LPS reproducibly developed fever at an ambient
temperature of 23°C. On the contrary, the old animals chose
significantly warmer positions in a thermal gradient than did the young
rats and only then became febrile (4). These observations
suggest that LPS may increase the thermal set point in old rats, which
can develop fever only at higher ambient temperature than the young
animals (4).
In the end, the expanding knowledge about the mechanisms of body
temperature control will hopefully enable researchers to develop
strategies of pharmacologically modulating the fever response to
various pyrogens.
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. Recent findings indicate that
IL-1 may communicate to the brain via a neural pathway involving activation of vagal afferents in addition to blood-borne routes. Thus
subdiaphragmatic vagotomy completely blocked the fever response to
intraperitoneal injection of IL-1 in rats, and this effect was
highest at low cytokine doses (8). In contrast, vagotomy failed to inhibit intravenous leptin-induced IL-1 expression in the
hypothalamus, suggesting that circulating leptin directly acts in the
brain independently of afferent vagus nerve input originating from the
subdiaphragmatic organs (10). A normal febrile response to
pyrogenic stimuli at thermoneutrality was also seen in obese Zucker
rats, which have a so-called fatty mutation in the leptin receptor gene
(13). Therefore, fatty mutation does not interrupt
febrigenic signaling from the periphery to the brain.
was attenuated by pretreatment either with IL-18 (5) or IL-10, which inhibited IL-1 production in the
hypothalamus and brain stem (18). Falling asleep is
probably the most convenient way to cope with a fever. As demonstrated
in two elegant studies, intracerebroventricular injection of IL-2,
IL-15, and IL-18 enhanced non-rapid eye movement sleep in rabbits and
rats, indicating a role for cytokines in the sleep response to
infection (16, 17). The potency of cytokines to induce
fever is normally controlled by binding to specific cytokine carriers
such as 
2-macroglobulin (2M). It was
shown in a recent paper that LPS-induced fever is attenuated in
2M-deficient mice compared with wild-type animals (7). At 1.5 h after injection of LPS, the plasma
concentration of TNF-, but not of IL-1 or IL-6, was significantly
lower in 2M
/ than in normal mice. These
findings suggest that a putative mechanism of 2M
involvement in fever is through the inhibition of TNF- clearance (7).
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. Scholz, Johannes-Müller-Institut für Physiologie, Humboldt-Universität, Charité, Tucholskystrasse 2, 10117 Berlin, Germany (E-mail: holger.scholz{at}charite.de).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00774.2002
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