Healthcare and Medicine Reference
In-Depth Information
1. Studies on IL-1 type I receptor (IL-1RI) knock-
out (KO) mice and IL-1R accessory protein (IL-1Rap)
KO mice have demonstrated that IL-1RI mediates
the fever response induced by a peripheral (ip) injec-
tion of IL-1
(with LPS or IL-1
for instance). The peripheral
administration of LPS induces IL-1
production in
meninges, choroid plexus macrophages, in some
perivascular cells, and in microglial cells shortly after
the ip injection (1-8 h). Constitutive expression of
. The fever response to LPS
is rather normal in these animals, suggesting that
TNF and other EPs can bypass the IL-1 system in
the generation of the febrile response.
2. IL-1
and IL-1
and IL-6/IL-6R in neuronal cell types has been
reported by some authors, but the matter is still
controversial. Receptors for the different EPs, partic-
ularly IL-1RI, are expressed constitutively in AH/
POA. Their expression is modulated by GC and EP,
particularly IL-1
KO mice show ''hyperresponsive'' fever
mostly in terms of magnitude of the effects in re-
sponse to IL-1
and IL-1
injection ip. Several differ-
. At the same time, pharmacologi-
cal doses of corticosterone block the LPS-induced
fever response and IL-1
ences in the LPS/IL-1
-induced cytokine
expression at both the mRNA and the gene product
level can be observed in these animals.
3. IL-6 KO mice are unable to mount a febrile
response on injection of IL-1
and IL-1
mRNAs ex-
pression in the hypothalamus, suggesting a causal
role for the hypothalamic production of cytokines
in fever induction.
The control by GC and EPs on the expression
of EPs/EP receptors is mostly transcriptional. The
promoter regions of EP genes contain an unusually
high number of GC receptor response elements. In
the case of IL-1
and TNF
or LPS in the periph-
ery. Only the parallel coinjection of IL-6 ip seems to
restore a sort of fever response to LPS ip injection.
The future availability of mice carrying a null muta-
tion of the genes coding for the intracellular proteins
that are downstream of IL-1Rap in the IL-1-signaling
pathway would further elucidate the cellular mecha-
nisms controlling the IL-1-mediated fever response.
, posttranscriptional con-
trol of GC at the mRNA and proteic level has been
demonstrated to be extremely important in control-
ling the cellular production of these EPs in immuno-
competent cells and the activation/secretion of the
mature form of these cytokines.
and TNF
A. Exogenous Pyrogens
The most used experimental model of fever re-
sponse in the presence of an endogenous stimulus
is represented by LPS injection in the periphery. This
model mimics a response to gram-negative bacterial
infections. Fever is also present during gram-positive
bacterial infections because macrophages can pro-
duce somnogenic and pyrogenic muramyl peptides
during the digestion of staphylococci fractions. Fur-
thermore, agents like turpentine are broadly used
as an experimental model of aseptic inflammation,
which is almost uniquely mediated by IL-1
C. Humoral Versus Neuronal
Mediators of Fever Induction
How does the brain ''sense'' EPs? This key ques-
tion has several answers. In fact, circulating proin-
flammatory cytokines can reach the brain via the
interaction with saturable carriers in the plexus
chorioideus. However, this mechanism would ac-
count for the entrance of a limited amount of
protein, eventually able to trigger local cytokine
production AH/POA. Several pathologic conditions
cause damage to the blood-brain barrier. In this
case the amount of circulating EPs reaching hypo-
thalamus could be higher. There is also a specialized
circumventricular organ—the organum vasculosum
lamina terminalis (OVLT)—located along the mar-
gin of the ventricular system that has fenestrated
capillaries and therefore direct contact with the
circulatory system.
The role of the OVLT has been demonstrated
in the case of peptides such as angiotensin II and
. How-
ever, the broadest spectrum of exogenous pyrogens
is offered by viral proteins or by the etiological agents
of parasitic infections such as schistosomiasis or ma-
laria. In case of viral infections, IFNs are the principal
responsible of the observed febrile response with IL-
contributing as EP.
B. Expression of EPs and Their
Receptors in the Hypothalamus
, and IL-6 gene expression can be
induced in AH/POA on peripheral immune challenge
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