Putative antihyperpyretic factor induced by LPS in spleen of guinea pigs

Abstract

We reported previously that the onset of LPS-induced fever, irrespective of its route of administration, is temporally correlated with the appearance of LPS in the liver and that splenectomy significantly increases both the febrile response to LPS and the uptake of LPS by Kupffer cells (KC). To further evaluate the role of the spleen in LPS fever production, we ligated the splenic vein and, 7 and 30 days later, monitored the core temperature changes over 6 h after intraperitoneal (ip) injection of LPS (2 microg/kg). Both the febrile response and the uptake of LPS by KC were significantly augmented. Like splenectomy, splenic vein ligation (SVL) increased the febrile response and LPS uptake by KC until the collateral circulation developed, suggesting that the spleen may normally contribute an inhibitory factor that limits KC uptake of LPS and thus affects the febrile response. Subsequently, to verify the presence of this factor, we prepared splenic extracts from guinea pigs pretreated with LPS (8 microg/kg ip) or pyrogen-free saline, homogenized and ultrafiltered them, and injected them intravenously into splenectomized (Splex) guinea pigs pretreated with LPS (8 microg/kg ip). The results confirmed our presumption that the splenic extract from LPS-treated guinea pigs inhibits the exaggerated febrile response and the LPS uptake by the liver of Splex guinea pigs, indicating the presence of a putative splenic inhibitory factor, confirming the participation of the spleen in LPS-induced fever, and suggesting the existence of a novel antihyperpyretic mechanism. Preliminary data indicate that this factor is a lipid.

Cyclooxygenase-1 or -2—which one mediates lipopolysaccharide-induced hypothermia?

“…Interestingly, large amounts of H-PGDS are present in the rat spleen (37), the organ in which the COX-1 pathway was activated at the onset of LPS hypothermia. Furthermore, Feleder et al (24,25) have recently shown that splenectomy or splenic vein ligation enhances LPS fever, and they have proposed that LPS causes the synthesis of a cryogenic lipid in the spleen. Our recent experiments (E. Pakai, A. Garami, T. B. Nucci, A.…”

Living history: Clark M. Blatteis

“…Using fluorescence-labeled endotoxin, he demonstrated that the onset of fever correlated with the appearance of endotoxin in liver Kupffer cells (19). In addition, he discovered that the interaction between endotoxin and liver Kupffer cells could be restrained by factors generated by the spleen (15) and that these splenic factors could reduce endotoxin uptake by liver Kupffer cells and the concomitant febrile responses induced by endotoxin (16). These results strongly substantiated the thesis that an interaction between bacterial endotoxin and liver Kupffer cells activates the complement system, which then produces C5a to induce fever.…”

Determination of prostaglandin profiles in lipopolysaccharide‐challenged guinea pig spleen

“…We also found that intraveneous injection of ultra‐filtered (molecular weight cutoff 10 kDa) splenic tissue extracts attenuates LPS‐induced fever, and the splenic inhibitory factor may exist in the protein‐free part of the spleen extract. These findings suggest that this factor is a lipid, perhaps a prostanoid (Feleder et al , ). Prostanoids are produced by the spleen, are released into the splenic vein, and thereby affect Kupffer cell activity.…”

“…). Previously, we proposed a novel, unrecognized, endogenous anti‐hyperpyretic mechanism that may limit exaggerated fevers (Feleder et al , , ). This hypothesis was based on data showing for the first time that the spleen may modulate the febrile response to lipopolysaccharide (LPS).…”