The role of the spleen in the febrile response induced by endotoxin in guinea pigs

The spleen plays a vital role in the host's protection against invading microorganisms. In spite of its fundamental participation and that of fever in the host defenses against infections, the role of the spleen in the febrile response has not yet been systematically investigated. We reported previously that splenectomy significantly increases both the febrile response to lipopolysaccharide (LPS) and the uptake of LPS by Kupffer cells (KC). In support, we also have shown that the ligation of the splenic vein of conscious guinea pigs challenged with LPS intraperitoneally (ip), augmented also both the febrile response and the uptake of LPS by KC until new collateral veins developed. This suggests that the spleen may normally contribute a factor that limits the KC uptake of LPS and thus modulates the febrile response. To verify the presence of a putative splenic antipyretic factor, we injected extract of spleens from guinea pigs pretreated with LPS and ultrafiltrated it, then injected it intravenously (iv) into splenectomized guinea pigs pre-treated with LPS ip. The results confirmed our presumption, viz., the splenic extract from LPS-treated guinea pigs inhibited the exaggerated febrile response observed in the splenectomized guinea pigs, supporting the presence of a putative antipyretic factor. The identity of the splenic factor(s) that may thus be released into the splenic vein, however, is (are) still uncertain, but the fact that the active principle passes through a microporous filter having a nominal molecular weight cutoff of 10,000 Da suggests that this factor could be a prostaglandin or a small peptide. Such factors have been described, e.g., PGD2, PGE2, PGF1α, thromboxane B2, atrial natriuretic peptide and β-endorphins. The identification of this putative splenic antihyperpyretic factor will be crucial for a better understanding of how the febrile response is controlled by the spleen to protect health by mitigating the potentially injurious effects of high fevers of the distressed host during infectious states. The aim of the present review is to focus on the new findings regarding the role that the spleen plays during the febrile response.