Modulation of Mouse Endotoxic Fever by Complement

Abstract

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 g/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 ϳ1°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 g/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 develop T c rises after i.p. LPS. Both CR2 ؉/؉ and CR2 ؊/؊ mice responded normally to i.p. LPS (1 g/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.

LPS-activated complement, not LPS per se, triggers the early release of PGE2by Kupffer cells

“…We infer from these data that the almost immediate appearance of PGE 2 in IVC plasma after the iportal injection of LPS supports the notion, advanced previously by us (5,6,28,30), that it may be mediated by C5a rapidly induced by LPS. On the other hand, its continued production in these animals, as manifested by its further, slower rise to a higher plateau at 15 min, its delayed elevation in the C-insufficient, LPS-treated guinea pigs (Fig.…”

“…Although not specifically demonstrated in the in vivo portions of this study, the in vitro results of experiment 3 strongly suggest that the targets of C5a, the anaphylatoxin specifically implicated in the febrile responses to intravenous and intraperitoneal LPS (28,30), are in all probability the Kc. Although hepatic stellate, sinusoidal endothelial, and mast cells also express its principal receptor, C5aR 1 , it is most abundant in Kc (48).…”

“…Hence, presumably, another factor rapidly evoked by LPS should drive this response. The complement (C) cascade is immediately activated in vivo by the presence of LPS (58), and we have recently reported that the anaphylatoxic complement component 5a (C5a) is an essential mediator of the febrile response to LPS (5,30). It was shown earlier that the in vitro production of PGE 2 by Kc is stimulated by C5a, whereas C depletion limits this production (15,41,48); Kc express abundant C5a receptors (14,48,61).…”

Mast cells are necessary for the hypothermic response to LPS-induced sepsis

“…LPS binds LPS-binding protein (LPB), forming a LPS-LPB complex. This complex then binds to Toll-like receptors (TLR) and complement (CЈ) receptors on cells of the innate immune system (5,22). NF-B-dependent transcription is subsequently upregulated, increasing production of cytokines and other immune effectors, including CЈ-mediated lysis for pathogen clearance (2).…”

Complement Depletion Renders C57BL/6 Mice Sensitive to the Bacillus anthracis Sterne Strain

“…To examine whether complement is involved in the control of the acapsular Sterne strain, C57BL/6 mice were given intraperitoneal injections of either phosphate-buffered saline (PBS) (vehicle control) or PBS containing cobra venom factor (CVF) as described previously (4,8). CVF enzymatically degrades complement and has been shown to result in nearly complete depletion of complement activity (9).…”