Complement is required for the induction of endotoxic fever in guinea pigs and mice

(1) Cobra venom factor (CVF)-induced hypocomplementemia dose-dependently attenuates the febrile responses of guinea pigs and mice to intraperitoneally (ip) but not to intravenously (iv) injected endotoxic bacterial lipopolysaccharide (LPS). (2) Iv but not ip LPS causes fever in complement component 3 (C3) gene-ablated mice, but neither iv nor ip LPS evokes a body core temperature (T_c) rise when WT and these mice's C5a receptors type 1 are blocked. C5 knockout mice also do not develop fever following either iv or ip LPS. C5a thus appears to be a critical mediator of LPS fever. (3) C5 knockouts develop fever in response to intracerebroventricularly (icv) injected LPS or prostaglandin (PG)E₂; the site of action of C5a is therefore peripheral rather than central. (4) The initiation of the febrile responses to both iv and ip LPS is temporally correlated with the appearance of LPS in the liver's Kupffer cells (Kc). (5) PGE₂ is released by liver in immediate response to the injection of CVF into the portal vein of anesthetized guinea pigs; its level rises quickly to its maximum. LPS injected similarly also evokes a quick release of PGE₂ from the liver; it, however, is prevented by prior hypocomplementation. (6) Neither LPS nor IL-1β induces PGE₂ release from Kc in vitro within the first hour after treatment, but serum C and C plus LPS or IL-1β very quickly trigger PGE₂ increases of similar magnitudes, catalyzed non-differentially by cyclooxygenase (COX)-1 and COX-2. Kc would thus appear to be the principal site of action of C5a, inducing the release of PGE₂. (7) PGE₂ is detectable in the plasma of conscious guinea pigs in temporal correlation with the onset of the T_c rise following ip LPS; cytokines appear significantly later. (8) Taken together, these results indicate that LPS-activated C, rather than LPS or IL-1β by itself, triggers PGE₂ release by Kc. This PGE₂ could be the factor that stimulates vagal afferents, thereby providing the signal to the brain that mediates the febrile response.