Kupffer cell-generated PGE2triggers the febrile response of guinea pigs to intravenously injected LPS

Abstract

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, PGE2could 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 μg/kg body wt iv) into conscious guinea pigs and measured their plasma levels of LPS, PGE2, TNF-α, IL-1β, and IL-6 before and 15, 30, 60, 90, and 120 min after LPS administration; Tcwas 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 Tcthat was temporally correlated with the elevation of plasma PGE2. KC depletion prevented the Tcand plasma PGE2rises and slowed the clearance of LPS from the blood. TNF-α was not detectable in plasma until 30 min and in IL-1β 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-α, the maximal level of which was increased approximately twofold in the KC-depleted animals. In a follow-up experiment, PGE2antiserum administered iv 10 min before LPS significantly attenuated the febrile response to LPS. Together, these results support the view that, in guinea pigs, PGE2rather than pyrogenic cytokines is generated by KCs in immediate response to iv LPS and triggers the febrile response.