COMPLEMENT REDUCTION IMPAIRS THE FEBRILE RESPONSE OF GUINEA-PIGS TO ENDOTOXIN

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.