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.
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.
Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Kyoko
K
Kagiwada
Dai
D
Chida
Tomoya
T
Sakatani
Masahide
M
Asano
Aya
A
Nambu
Shigeru
S
Kakuta
Yoichiro
Y
Iwakura
D000818:Animals; D001921:Brain / Q000276:immunology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D005334:Fever / Q000276:immunology* / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics* / Q000276:immunology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin