Interleukin (IL)-6, but Not IL-1, Induction in the Brain Downstream of cyclooxygenase-2 Is Essential for the Induction of Febrile Response Against Peripheral IL-1alpha

Endocrinology. 2004 Nov;145(11):5044-8. doi: 10.1210/en.2004-0054. Epub 2004 Jul 22.


IL-1 is an endogenous pyrogen produced upon inflammation or infection. Previously, we showed that, upon injection with turpentine, IL-1 is induced in the brain in association with the development of fever. The role of endogenous IL-1 in the brain and the signaling cascade to activate thermosensitive neurons, however, remain to be elucidated. In this report, febrile response was analyzed after peripheral injection of IL-1alpha. We found that a normal febrile response was induced even in IL-1alpha/beta-deficient mice, indicating that production of IL-1 in the brain is not necessarily required for the response. In contrast, IL-6-deficient mice did not exhibit a febrile response. Cyclooxygenase (Cox)-2 expression in the brain was strongly induced 1.5 h after injection of IL-1alpha, whereas IL-6 expression was observed 3 h after the injection. Cox-2 expression in the brain was not influenced by IL-6 deficiency, whereas indomethacin, an inhibitor of cyclooxygenases, completely inhibited induction of IL-6. These observations suggest a mechanism of IL-1-induced febrile response in which IL-1 in the blood activates Cox-2, with the resulting prostaglandin E(2) inducing IL-6 in the brain, leading to the development of fever.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / immunology*
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Female
  • Fever / immunology*
  • Fever / metabolism
  • Indomethacin / pharmacology
  • Interleukin-1 / genetics*
  • Interleukin-1 / immunology
  • Interleukin-1 / pharmacology
  • Interleukin-6 / genetics*
  • Interleukin-6 / immunology
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Signal Transduction / immunology


  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Interleukin-1
  • Interleukin-6
  • Isoenzymes
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Indomethacin