LPS-activated complement, not LPS per se, triggers the early release of PGE2 by Kupffer cells.
The intravenous injection of LPS rapidly evokes fever. We have hypothesized that its onset is mediated by prostaglandin (PG)E(2) quickly released by Kupffer cells (Kc). LPS, however, does not stimulate PGE(2) production by Kc as rapidly as it induces fever; but complement (C) activated by LPS could be the exciting agent. To test this hypothesis, we injected LPS (2 or 8 microg/kg) or cobra venom factor (CVF, an immediate activator of the C cascade that depletes its substrate, ultimately causing hypocomplementemia; 25 U/animal) into the portal vein of anesthetized guinea pigs and measured the appearance of PGE(2), TNF-alpha, IL-1beta, and IL-6 in the inferior vena cava (IVC) over the following 60 min. LPS (at both doses) and CVF induced similar rises in PGE(2) within the first 5 min after treatment; the rises in PGE(2) due to CVF returned to control in 15 min, whereas PGE(2) rises due to LPS increased further, then stabilized. LPS given 3 h after CVF to the same animals also elevated PGE(2), but after a 30- to 45-min delay. CVF per se did not alter basal PGE(2) and cytokine levels and their responses to LPS. These in vivo effects were substantiated by the in vitro responses of primary Kc from guinea pigs to C (0.116 U/ml) and LPS (200 ng/ml). These results indicate that LPS-activated C rather than LPS itself triggers the early release of PGE(2) by Kc.
Perlik
Vit
V
Dept. of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA.
Li
Zhongua
Z
Goorha
Sarita
S
Ballou
Leslie R
LR
Blatteis
Clark M
CM
D000818:Animals; D003167:Complement Activation / Q000502:physiology*; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004546:Elapid Venoms / Q000008:administration & dosage / Q000494:pharmacology; D006168:Guinea Pigs; D007275:Injections, Intravenous; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D013997:Time Factors
D003169:Complement Inactivator Proteins; D004546:Elapid Venoms; D008070:Lipopolysaccharides; C016310:cobra venom factor; D015232:Dinoprostone