Cytokines and cytokine inducers stimulate prostaglandin E₂ entry into the brain

Abstract.

Cytokine inducers and cytokines increase the circulating level of prostaglandin E₂ (PGE₂) during the acute-phase immune response. This occurs simultaneously with the onset of fever, indicating that brain levels of PGE₂ also increase. This raises the possibility that PGE₂ produced in the peripheral circulation, not necessarily at distant sites from the brain, may penetrate the brain and be present in the cerebrospinal fluid (CSF). Blood and CSF levels of PGE₂ in rabbits were measured by radioimmunoassay during fever stimulated in response to lipopolysaccharide (LPS), polyinosinic:polycytidylic acid (poly I:C) and interleukin-1 (IL-1) given i.v. The effect of the prostaglandin synthesis inhibitor ketoprofen on these parameters was also studied. In addition, the level of radioactivity in the CSF was measured following the administration of [¹²⁵I]-labelled PGE₂ i.v. during fever induced by LPS, poly I:C, IL-1 or tumor necrosis factor alpha (TNFα). Both LPS and poly I:C stimulated an increase in plasma and CSF levels of PGE₂ over a 5-h period with a peak at 60 min and 90 min, respectively, which occurred in parallel with the changes in body temperature. Ketoprofen abolished the rise in plasma and CSF PGE₂ levels and the rise in body temperature in response to LPS, poly I:C and IL-1. In experiments where animals were given [¹²⁵I]-labelled PGE₂ i.v., radioactivity well above the background level was measured in samples of CSF collected from LPS-, poly I:C-, IL-1- or TNFα-pretreated animals. In contrast the radioactivity present in samples of CSF perfusate collected from control (saline-treated) animals was indistinguishable from the background level. These data indicate that cytokine inducers and cytokines increase the mass level of PGE₂ in blood and CSF and also increases the entry, from the peripheral circulation, of radiolabelled PGE₂ into the third cerebral ventricle.