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Articles in PresS, published online ahead of print October 24, 2002
Am J Physiol Regu Physiol, 10.1152/ajpregu.00570.2002
Submitted on September 16, 2002
Accepted on October 22, 2002
1 Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA
2 Barrow Neurological Institute, Neurology Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA
* To whom correspondence should be addressed. E-mail: aromano{at}chw.edu.
Prostaglandin (PG) E2 is a principal downstream mediator of fever and other symptoms of systemic inflammation. Its inactivation occurs in peripheral tissues, primarily the lungs and liver, via carrier-mediated cellular uptake and enzymatic oxidation. We hypothesized that inactivation of PGE2 is suppressed during lipopolysaccharide (LPS) fever, and that transcriptional down-regulation of PGE2 carriers and catabolizing enzymes contributes to this suppression. Fever was induced in inbred Wistar Kyoto rats by intravenous LPS (50 µg/kg); the controls received saline. Samples of the liver, lungs, and hypothalamus were harvested 0, 0.5, 1.5, and 5 h postinjection. The expression of the two principal transmembrane PGE2 carriers (PG transporter and multispecific organic anion transporter) and the two key PGE2-inactivating enzymes [15-hydroxy-PG dehydrogenase (15-PGDH) and carbonyl reductase] was quantified by RT-PCR. All four genes of interest were down-regulated in peripheral tissues (but not the brain) during fever. Most remarkably, the expression of hepatic 15-PGDH was decreased 26 fold 5 h post-LPS, whereas expression of pulmonary 15-PGDH was down-regulated (as much as 18 fold) throughout the entire febrile course. The transcriptional down-regulation of several proteins involved in PGE2 inactivation, first reported here, is an unrecognized mechanism of systemic inflammation. By increasing the blood-brain gradient of PGE2, this mechanism likely facilitates penetration of PGE2 into the brain and prevents its elimination from the brain.
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