Cyclooxygenase-2 mediates the febrile response of mice to interleukin-1beta

Brain Res. 2001 Aug 10;910(1-2):163-73. doi: 10.1016/s0006-8993(01)02707-x.

Abstract

Various lines of evidence have implicated cyclooxygenase (COX)-2 as a modulator of the fever induced by the exogenous pyrogen lipopolysaccharide (LPS). Thus, treatment with specific inhibitors of COX-2 suppresses the febrile response without affecting basal body (core) temperature (T(c)). Furthermore, COX-2 gene-ablated mice are unable to develop a febrile response to intraperitoneal (i.p.) LPS, whereas their COX-1-deficient counterparts produce fevers not different from their wild-type (WT) controls. To extend the apparently critical role of COX-2 for LPS-induced fevers to fevers produced by endogenous pyrogens, we studied the thermal responses of COX-1- and COX-2 congenitally deficient mice to i.p. and intracerebroventricular (i.c.v.) injections of recombinant murine (rm) interleukin (IL)-1beta. We also assessed the effects of one selective COX-1 inhibitor, SC-560, and two selective COX-2 inhibitors, nimesulide (NIM) and dimethylfuranone (DFU), on the febrile responses of WT and COX-1(-/-) mice to LPS and rmIL-1beta, i.p. Finally, we verified the integrity of the animals' responses to PGE2, i.c.v. I.p. and i.c.v. rmIL-1beta induced similar fevers in WT and COX-1 knockout mice, but provoked no rise in the T(c)s of COX-2 null mutants. The fever produced in WT mice by i.p. LPS was not affected by SC-560, but it was attenuated and abolished by NIM and DFU, respectively, while that caused by i.p. rmIL-1beta was converted into a T(c) fall by DFU. There were no differences in the responses to i.c.v. PGE2 among the WT and COX knockout mice. These results, therefore, further support the notion that the production of PGE2 in response to pyrogens is critically dependent on COX-2 expression.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Body Temperature / drug effects
  • Body Temperature / physiology
  • Brain / drug effects*
  • Brain / enzymology
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Dinoprostone / metabolism*
  • Fever / chemically induced
  • Fever / enzymology*
  • Fever / physiopathology
  • Inflammation / metabolism
  • Inflammation / physiopathology
  • Injections, Intraventricular
  • Interleukin-1 / metabolism
  • Interleukin-1 / pharmacology*
  • Interleukin-1beta
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Lipopolysaccharides / metabolism
  • Lipopolysaccharides / pharmacology
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Neuroimmunomodulation / drug effects
  • Neuroimmunomodulation / physiology
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Pyrogens / metabolism*
  • Pyrogens / pharmacology

Substances

  • Interleukin-1
  • Interleukin-1beta
  • Isoenzymes
  • Lipopolysaccharides
  • Membrane Proteins
  • Peptide Fragments
  • Pyrogens
  • interleukin-1beta (163-171)
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, mouse
  • Dinoprostone