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Published online before print September 22, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0106064

Received for publication January 27, 2006.
Revised July 17, 2006.
Accepted for publication August 2, 2006.

Article

Endotoxin fever in granulocytopenic rats: evidence that brain cyclooxygenase-2 is more important than circulating prostaglandin E₂

Eva Tavares ^*, Francisco J. Miñano ^*@, Rosario Maldonado ^*, and Michael J. Dascombe

*Research Unit, Laboratory for Clinical and Experimental Pharmacology, University Hospital of Valme, Seville, Spain; Department of Pharmacology, Paediatrics and Radiology, Faculty of Medicine, University of Seville, Seville, Spain; and Faculty of Life Sciences, University of Manchester, Manchester, UK

^@ To whom correspondence should be addressed. E-mail: jminano{at}us.es.

	Abstract

PGE₂ is a recognized mediator of many fevers, and cyclooxygenase (COX) is the major therapeutic target for antipyretic therapy. The source, as well as the site of action of PGE₂, as an endogenous pyrogen, is widely accepted as being central, but PGE₂ in the circulation, possibly from leukocytes, may also contribute to the development of fever. However, bacterial infections are important causes of high fever in patients receiving myelosuppressive chemotherapy, and such fevers persist despite the use of COX inhibitors. In the study reported here, the febrile response to bacterial LPS was measured in rats made leukopenic by cyclophosphamide. A striking increase in LPS fever occurred in these granulocytopenic rats when compared with febrile responses in normal animals. Unlike LPS fever in normal rats, fever in granulocytopenic rats was neither accompanied by an increase in blood PGE₂ nor inhibited by ibuprofen. Both leukopenic and normal rats showed LPS-induced COX-2-immunoreactivity in cells associated with brain blood vessels. Furthermore, LPS induced an increase of PGE₂ in cerebrospinal fluid. Induction of COX-2-expression and PGE₂ production was inhibited by ibuprofen in normal but not in leukopenic rats. Although the results presented are, in part, confirmatory, they add new information to this field and open a number of important questions as yet unresolved. Overall, the present results indicate that, in contrast to immunocompetent rats, leukocytes and/or other mechanisms other than PGE₂ are implicated in the mechanisms restricting and reducing the enhanced febrile response to endotoxin in immunosuppressed hosts.

Key Words: cyclophoshamide • ibuprofen • lypopolysaccharide • subfornical organ