INTERLEUKIN-1 RECEPTOR ANTAGONIST INHIBITS ENDOTOXIN FEVER AND SYSTEMIC INTERLEUKIN-6 INDUCTION IN THE RAT

Although a number of studies indicate that the pyrogenic activity of l ipopolysaccharide (LPS) and/or interleukin (IL)-1 is mediated via indu ction of IL-6, this has been questioned by recent evidence demonstrati ng a dissociation between fever and circulating IL-6. The present stud y reexamines this relationship by use of human recombinant interleukin -1 receptor antagonist (IL-1ra). Injection of LPS (100 mu g/kg ip) int o rats induced fever (2.0 degrees C) that was significantly inhibited (P < 0.05) when IL-1ra (16 mg/kg ip) was given 1 and 2 h after LPS. Th e rise in plasma IL-6 preceded the febrile response by 1-1.5 h and, al though the concentrations of bioactive IL-6 in plasma and cerebrospina l fluid (CSF) were not reduced at 4 h, at 2 h plasma and CSF IL-6 bioa ctivity was inhibited by 80 and 70%, respectively, after a single inje ction of IL-1ra (16 mg/kg ip). Intracerebroventricular injection of IL -1ra (200 mu g/rat) inhibited LPS fever but did not affect the plasma IL-6 bioactivity measured 2 or 4 h after intraperitoneal LPS. These da ta show that peripheral IL-1 plays a part in the induction of both fev er and the rise in plasma IL-6 that precedes it, and that IL-1 within the brain is also important in the induction of fever by LPS.