Clark M. Blatteis

We reported previously that the onset of LPS-induced fever, irrespective of its route of administration, is temporally correlated with the appearance of LPS in the liver and that splenectomy significantly increases both the febrile response to LPS and the uptake of LPS by Kupffer cells (KC). To further evaluate the role of the spleen in LPS fever production, we ligated the splenic vein and, 7 and 30 days later, monitored the core temperature changes over 6 h after intraperitoneal (ip) injection of LPS (2 μg/kg). Both the febrile response and the uptake of LPS by KC were significantly augmented. Like splenectomy, splenic vein ligation (SVL) increased the febrile response and LPS uptake by KC until the collateral circulation developed, suggesting that the spleen may normally contribute an inhibitory factor that limits KC uptake of LPS and thus affects the febrile response. Subsequently, to verify the presence of this factor, we prepared splenic extracts from guinea pigs pretreated with LPS (8 μg/kg ip) or pyrogen-free saline, homogenized and ultrafiltered them, and injected them intravenously into splenectomized (Splex) guinea pigs pretreated with LPS (8 μg/kg ip). The results confirmed our presumption that the splenic extract from LPS-treated guinea pigs inhibits the exaggerated febrile response and the LPS uptake by the liver of Splex guinea pigs, indicating the presence of a putative splenic inhibitory factor, confirming the participation of the spleen in LPS-induced fever, and suggesting the existence of a novel antihyperpyretic mechanism. Preliminary data indicate that this factor is a lipid.

It was recently reported that the complement system may be critically involved in the febrile response of guinea pigs to systemic, particularly intraperitoneally (i.p.) injected, lipopolysaccharides (LPS). The present study was designed to identify which component(s) of the complement cascade may be specifically critical. To this end, we used mice with C3, C5, and CR2 gene deletions. To assess preliminarily the suitability of mice for such a study, we replicated our earlier studies with guinea pigs. Thus, to verify initially whether complement is similarly involved in the febrile response of wild-type (C57BL/6J) mice to i.p. LPS (Escherichia coli, 1 μg/mouse), we depleted complement with cobra venom factor (CVF; 7 U/mouse, intravenously [i.v.]). These animals did not develop fever, whereas the core temperature (T_c) of CVF vehicle-treated controls rose ∼1°C by 80 min postinjection and then gradually abated over the following 2.5 h, confirming the involvement of complement in fever production after i.p. LPS injection and the suitability of this species for these studies. C3- and C5-sufficient (C3^+/+and C5^+/+) mice also developed 1°C fevers within 80 min after i.p. LPS (1 or 2 μg/mouse) injection. These fevers were totally prevented by CVF (10 U/mouse, i.v.) pretreatment. C3- and C5-deficient (C3^−/−and C5^−/−) mice were also unable to developT_crises after i.p. LPS. Both CR2^+/+and CR2^−/−mice responded normally to i.p. LPS (1 μg/mouse). These data indicate that C5, but not C3d acting through CR2, may play a critical role in the febrile response of mice to i.p. LPS.

Fever is thought to be caused by endogenous pyrogenic cytokines, which are elaborated and released into the circulation by systemic mononuclear phago

Heat exposure, infectious fever and water deprivation are stressors that, individually, produce disturbances in more than one regulated system, calling for diverse compensatory responses. A potential conflict is created when these stimuli are combined and impose concurrent stressful loads on the body because the homeostatic defenses mobilized against one are also partly needed against the other stressors. To learn how the competing demands of combined stressors for shared regulatory systems are met, rabbits were exposed to 32°C and 37°C (heat), administered lipopolysaccharide (Salmonella enteritidis LPS, 2 µg/kg, i.v.) in temperatures of 22°C or 27°C, or water-deprived for 1 or 2 days in 22°C or 27°C, in separate experiments. The corresponding controls were exposed to 22°C or 27°C, administered pyrogen-free saline i.v. in 22°C or 27°C, or normally hydrated in 22°C or 27°C. In subsequent experiments, two or all three of these treatments were applied concurrently. Core and ear skin temperatures and respiratory rates were monitored continuously. The results indicated that the concomitant needs of moderate heat exposure, fever and 1 day of water deprivation were generally met by the regulatory systems involved, but different patterns of thermoeffector activities were evoked and the eventual body temperature changes produced were different under each condition. However, when the test conditions were severe, their combined needs were not met adequately and the eventual compensatory response depended not only on the particular stimulus intensity, but also on the immediate importance for survival of the functions being defended. Thus, dehydration was the most dangerous factor to the physiological integrity of the animals. In sum, conflicting physiological stimuli appear to result in responses that are different from the responses to a single perturbation, the eventual output representing the resultant of the inputs rather than a singular output dictated by one dominant drive to the exclusion of the others.

Abstract: Fever is induced in response to the entrance of pathogenic microorganisms into the body and is thought to be mediated by cytokines. Because these pathogens most commonly invade the body through its natural barriers and because body temperature is regulated centrally, these mediators are presumed to be produced peripherally and transported by the bloodstream to the brain, to act. It is generally considered that their febrigenic messages are further modulated there by prostaglandin E₂ (PGE₂). However, the detailed mechanism by which these cytokines signal the brain and activate the febrile response is not yet clear. Indeed, the specific role of each cytokine has been difficult to establish due to complex interactions among them. Furthermore, recent evidence suggests that different pyrogens may induce different cytokines; for example, i.v. LPS (a model of systemic bacterial infection) induces large increases in IL‐6, but only small rises in IL‐1 and TNFα plasma levels. Moreover, their appearance lags the fever onset. We recently found that subdiaphragmatic vagotomy, decomplementation, and blockade of Kupffer cells suppress the febrile response of guinea pigs to i.v. LPS, and that i.v. LPS rapidly stimulates the release of norepinephrine (NE) and, hence, of PGE₂ in their preoptic‐anterior hypothalamus (POA, the brain region containing the thermoregulatory controller). Based on these and other data in the literature, we hypothesize that LPS fever may be initiated as follows: i.v., LPS → complement → Kupffer cells → cytokines?→ vagal afferents → n. tractus solitarius?→ A1/A2 cell groups?→ ventral noradrenergic bundle?→ POA → NE → PGE₂→ fever.