LPS-activated complement, not LPS per se, triggers the early release of PG[E.sub.2] by Kupffer cells

The intravenous injection of LPS rapidly evokes fever. We have hypothesized that its onset is mediated by prostaglandin (PG)[E.sub.2] quickly released by Kupffer cells (Kc). LPS, however, does not stimulate PG[E.sub.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 [micro]g/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 PG[E.sub.2], TNF-[alpha], IL-1[beta], and IL-6 in the inferior vena cava (IVC) over the following 60 min. LPS (at both doses) and CVF induced similar rises in PG[E.sub.2] within the first 5 min after treatment; the rises in PG[E.sub.2] due to CVF returned to control in 15 min, whereas PG[E.sub.2] rises due to LPS increased further, then stabilized. LPS given 3 h after CVF to the same animals also elevated PG[E.sub.2], but after a 30- to 45-min delay. CVF per se did not alter basal PG[E.sub.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 PG[E.sub.2] by Kc. liver; fever; portal vein cannulation; cobra venom factor; pyrogenic cytokines