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

Abstract

The intravenous injection of LPS rapidly evokes fever. We have hypothesized that its onset is mediated by prostaglandin (PG)E2 quickly released by Kupffer cells (Kc). LPS, however, does not stimulate PGE2 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 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 PGE2, TNF-␣, IL-1␤, and IL-6 in the inferior vena cava (IVC) over the following 60 min. LPS (at both doses) and CVF induced similar rises in PGE2 within the first 5 min after treatment; the rises in PGE2 due to CVF returned to control in 15 min, whereas PGE2 rises due to LPS increased further, then stabilized. LPS given 3 h after CVF to the same animals also elevated PGE2, but after a 30-to 45-min delay. CVF per se did not alter basal PGE2 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 PGE2 by Kc. liver; fever; portal vein cannulation; cobra venom factor; pyrogenic cytokines FEVER DEVELOPS QUICKLY AFTER the intravenous bolus administration of a pyrogenic dose of LPS to conscious guinea pigs, rats, and other species, but the afferent mechanism that induces this response is controversial. It is generally thought that it is mediated by pyrogenic cytokines produced secondarily in response to the LPS challenge, rather than by its direct action. Tumor necrosis factor-␣ (TNF-␣), IL-1␤, and IL-6 are the major cytokines implicated in this response (9). There is, however, a temporal disconnect between the first appearance of these cytokines and the onset of the febrile response to intravenous LPS; that is, fever appears within 10 -15 min (13, 51) whereas TNF-␣, the first cytokine to appear, is not detectable until 30 min after LPS treatment (18,23,24,39). This temporal discrepancy is less evident after the intraperitoneal administration of low to moderate doses of LPS, when the latency of fever onset is ϳ60 min but becomes evident also when higher doses are administered, when the onset latency approaches that after intravenous LPS (7).We have shown previously that the onsets of the febrile responses to intravenous and intraperitoneal LPS are correlated with the appearance of LPS in the liver's Kupffer cells (Kc) (31), the body's principal clearinghouse of LPS (16,34,45) and source of pyrogenic cytokines (10). As cytokines are not constitutively expressed by Kc and their de novo production occurs after some delay (32), we and others have proposed, to account for the promptness of the febrile response to intravenous LPS, that the peripheral pyrogenic signal could be transmitted to the preoptic-anterior...

Preoptic norepinephrine mediates the febrile response of guinea pigs to lipopolysaccharide

“…Indeed, ample data have implicated the vagus, especially its hepatic branch afferents, as the carrier of peripheral pyrogenic signals to the brain stem (60, 63; for reviews, see Refs. 19 and 61) and identified PGE 2 released by Kupffer cells stimulated by LPS-activated complement component 5a as this fever signal (40,54; for reviews, see Refs. 7,8,36,57).…”

Neonatal programming of innate immune function

“…The vagus nerve plays a large role in the activation of HPA responses following peripheral inflammatory stimuli (31,44), and acute-phase mediators released from the liver can activate it sufficiently rapidly to precede the synthesis and release of cytokines responsible for fever (10,51,65). However, Fos immunoreactivity in the nucleus of the solitary tract (where vagal afferents terminate) was attenuated, not enhanced, in response to LPS in neonatally LPS-treated adults.…”

Early Life Activation of Toll-Like Receptor 4 Reprograms Neural Anti-Inflammatory Pathways

“…Vagal afferent fibers have been previously suggested to mediate part of the neuroimmune response to low doses of LPS (Romanovsky et al, 1997a;Hansen et al, 2000a;Konsman et al, 2000;Hosoi et al, 2005), but direct or indirect (Visintin et al, 2001;Zarember and Godowski, 2002;Hosoi et al, 2005;Perlik et al, 2005) stimulation of TLR4s to activate vagal afferents does not appear to be involved in the programming response. There was no evidence for early activation of the NTS where vagal afferents terminate, nor did hepatic vagotomy reduce the early corticosterone surge in the postnatal LPS-treated adult.…”