E. Sehic et al., COMPLEMENT REDUCTION IMPAIRS THE FEBRILE RESPONSE OF GUINEA-PIGS TO ENDOTOXIN, American journal of physiology. Regulatory, integrative and comparative physiology, 43(6), 1998, pp. 1594-1603
Although it is generally believed that circulating exogenous pyrogens
[e.g., lipopolysaccharides (LPS)] induce fever via the mediation of en
dogenous pyrogens (EP) such as cytokines, the first of these, tumor ne
crosis factor-alpha, is usually not detectable in blood until at least
30 min after intravenous administration of LPS, whereas the febrile r
ise begins within 15 min after its administration. Moreover, although
abundant evidence indicates that circulating LPS is cleared primarily
by liver macrophages [Kupffer cells (KC)], these do not secrete EP in
immediate response. This would imply that other factors, presumably ev
oked earlier than EP, may mediate the onset of the febrile response to
intravenous LPS. It is well known that blood-borne LPS very rapidly a
ctivates the intravascular complement (C) system, some components of w
hich in turn stimulate the quick release into blood of various substan
ces that have roles in the acute inflammatory reaction. KC contain rec
eptors for C components and are in close contact with afferent vagal t
erminals in the liver; the involvement of hepatic vagal afferents in L
PS-induced fever has recently been shown. In this study, we tested the
hypothesis that the initiation of fever by intravenous LPS involves,
sequentially, the C system and KC. To test this postulated mechanism,
we measured directly the levels of prostaglandin E-2 (PGE(2)) in the i
nterstitial fluid of the preoptic anterior hypothalamus (POA), the pre
sumptive site of the fever-producing controller of conscious guinea pi
gs over their entire febrile course, before and after C depletion by c
obra venom factor (CVF) and before and after elimination of KC by gado
linium chloride (GdCl3). CVF and GdCl3 pretreatment each individually
attenuated the first of the biphasic core temperature (T-c) rises afte
r intravenous LPS, inverted the second into a T-c fall, and greatly re
duced the usual fever-associated increase in POA PGE(2). We conclude,
therefore, that C activation may indeed be pivotal in the induction of
fever by intravenous LPS and that substance(s) generated presumably b
y KC in almost immediate reaction to the presence of LPS and/or C may
transmit pyrogenic signals via hepatic vagal afferents to the POA, whe
re they rapidly induce the production of PGE(2) and, hence, fever.