Cyclooxygenase-2/microsomal prostaglandin E synthase-1 complex in the preoptic-anterior hypothalamus of the mouse: involvement through fever to intravenous lipopolysaccharide.
OBJECTIVE
Prostaglandin E₂ (PGE₂) is now well established as a central effector of pyrogen fever. However, questions remain on the source, local vs. blood-borne, of the compound for the early phase of the typically biphasic fever (Phases 1 and 2) to i.v. pyrogens. To verify the role of centrally formed PGE₂, we examined the cyclooxygenase (COX)/prostaglandin E synthase (PGES) complex through fever to i.v. lipopolysaccharide (LPS).


METHODS
Experiments were carried out in the conscious mouse and LPS effect was ascertained on all steps of expression - gene, protein, catalytic activity - of individual enzymes. The analysis was limited to the preoptic-anterior hypothalamus (AH/POA).


RESULTS
We found upregulation of the COX2 transcript together with an upward trend for the mPGES1 transcript during Phase 1. Coincidentally, there was a progressive increase in COX2 and mPGES1 protein expression through Phases 1 and 2. Catalytic activity for COX1 and COX2 combined was instead enhanced only in Phase 2, while mPGES1 activity remained steady at an intrinsically high level. Other COX and PGES enzymes were not modified through either Phase, and COX2/mPGES1 changes subsided with fever defervescence.


CONCLUSIONS
The findings confirm a key function of COX2 and mPGES1 for the synthesis of pyrogenic PGE₂ and, at the same time, document their early response to LPS. We conclude that locally formed PGE₂ in AH/POA is qualified for a role in the initiation of fever.
Gaetano
L
L
Scuola Superiore Sant'Anna, Pisa, Italy.
Watanabe
K
K
Barogi
S
S
Coceani
F
F
D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism; D005334:Fever / Q000276:immunology*; D007032:Hypothalamus, Anterior / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology*; D011301:Preoptic Area / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases
D007527:Isoenzymes; D008070:Lipopolysaccharides; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone