Prostaglandin E(2)-synthesizing enzymes in fever: differential transcriptional regulation.
The febrile response to lipopolysaccharide (LPS) consists of three phases (phases I-III), all requiring de novo synthesis of prostaglandin (PG) E(2). The major mechanism for activation of PGE(2)-synthesizing enzymes is transcriptional upregulation. The triphasic febrile response of Wistar-Kyoto rats to intravenous LPS (50 microg/kg) was studied. Using real-time RT-PCR, the expression of seven PGE(2)-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) A(2)-IIA --> COX-2 --> mPGES, in both the periphery and brain. Phase III was accompanied by the induction of cytosolic (c) PLA(2)-alpha in the hypothalamus, further upregulation of sPLA(2)-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 sPLA(2)-V nor cPGES was induced by LPS. The high magnitude of upregulation of mPGES and sPLA(2)-IIA (1,257-fold and 133-fold, respectively) makes these enzymes attractive targets for anti-inflammatory therapy.
Ivanov
Andrei I
AI
Trauma Research, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, USA.
Pero
Ralph S
RS
Scheck
Adrienne C
AC
Romanovsky
Andrej A
AA
D000818:Animals; D015232:Dinoprostone / Q000096:biosynthesis*; D005334:Fever / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010741:Phospholipases A / Q000096:biosynthesis / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D015232:Dinoprostone