Prostaglandin E2-Synthesizing Enzymes In Fever: Differential Transcriptional Regulation

Department

neurobiology

Document Type

Article

Abstract

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-α 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.

Publication Date

11-1-2002

Publication Title

American Journal of Physiology - Regulatory Integrative and Comparative Physiology

ISSN

03636119

Volume

283

Issue

5

First Page

R1104

Last Page

R1117

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