CALL FOR PAPERS Physiology and Pharmacology of Temperature Regulation Kupffer cell-generated PGE2 triggers the febrile response of guinea pigs to intravenously injected LPS

Li, Zhonghua, Vit Perlik, Carlos Feleder, Ying Tang, and Clark M. Blatteis. Kupffer cell-generated PGE2 triggers the febrile response of guinea pigs to intravenously injected LPS. Am J Physiol Regul Integr Comp Physiol 290: R1262–R1270, 2006. First published January 12, 2006; doi:10.1152/ajpregu.00724.2005.—Because the onset of fever induced by intravenously (iv) injected bacterial endotoxic lipopolysaccharides (LPS) precedes the appearance in the bloodstream of pyrogenic cytokines, the presumptive peripheral triggers of the febrile response, we have postulated previously that, in their stead, PGE2 could be the peripheral fever trigger because it appears in blood coincidentally with the initial body core temperature (Tc) rise. To test this hypothesis, we injected Salmonella enteritidis LPS (2 g/kg body wt iv) into conscious guinea pigs and measured their plasma levels of LPS, PGE2, TNF, IL-1 , and IL-6 before and 15, 30, 60, 90, and 120 min after LPS administration; Tc was monitored continuously. The animals were untreated or Kupffer cell (KC) depleted; the essential involvement of KCs in LPS fever was shown previously. LPS very promptly ( 10 min) induced a rise of Tc that was temporally correlated with the elevation of plasma PGE2. KC depletion prevented the Tc and plasma PGE2 rises and slowed the clearance of LPS from the blood. TNFwas not detectable in plasma until 30 min and in IL-1 and IL-6 until 60 min after LPS injection. KC depletion did not alter the times of appearance or magnitudes of rises of these cytokines, except TNF, the maximal level of which was increased approximately twofold in the KC-depleted animals. In a follow-up experiment, PGE2 antiserum administered iv 10 min before LPS significantly attenuated the febrile response to LPS. Together, these results support the view that, in guinea pigs, PGE2 rather than pyrogenic cytokines is generated by KCs in immediate response to iv LPS and triggers the febrile response.