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1 Trauma Research and 2 Neurology Research, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013
The febrile response to
lipopolysaccharide (LPS) consists of three phases (phases
I-III), all requiring de novo synthesis of prostaglandin (PG)
E2. The major mechanism for activation of PGE2-synthesizing enzymes is transcriptional upregulation.
The triphasic febrile response of Wistar-Kyoto rats to intravenous LPS
(50 µg/kg) was studied. Using real-time RT-PCR, the expression of
seven PGE2-synthesizing enzymes in the LPS-processing
organs (liver and lungs) and the brain "febrigenic center"
(hypothalamus) was quantified. Phase I involved
transcriptional upregulation of the functionally coupled cyclooxygenase
(COX)-2 and microsomal (m) PGE synthase (PGES) in the liver and lungs.
Phase II entailed robust upregulation of all enzymes of the
major inflammatory pathway, i.e., secretory (s) phospholipase (PL)
A2-IIA 
COX-2 mPGES, in both the periphery and
brain. Phase III was accompanied by the induction of
cytosolic (c) PLA2-
in the hypothalamus, further upregulation of sPLA2-IIA and mPGES in the hypothalamus and
liver, and a decrease in the expression of COX-1 and COX-2 in all
tissues studied. Neither sPLA2-V nor cPGES was induced by
LPS. The high magnitude of upregulation of mPGES and
sPLA2-IIA (1,257-fold and 133-fold, respectively) makes
these enzymes attractive targets for anti-inflammatory therapy.
cyclooxygenases; phospholipases; terminal prostaglandin E synthases; lipopolysaccharide; febrile phases
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