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Physiology and Pharmacology of Temperature Regulation

Expanding the febrigenic role of cyclooxygenase-2 to the previously overlooked responses

¹Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and ²Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

Submitted 26 May 2005 ; accepted in final form 28 July 2005

ABSTRACT

Previous studies on the role of cyclooxygenase (COX)-1 and -2 in fever induced by intravenous LPS have failed to investigate the role of these isoenzymes in the earliest responses: monophasic fever (response to a low, near-threshold dose of LPS) and the first phase of polyphasic fever (response to higher doses). We studied these responses in 96 mice that were COX-1 or COX-2 deficient (–/–) or sufficient (+/+). Each mouse was implanted with a temperature telemetry probe into the peritoneal cavity and a jugular catheter. The study was conducted at a tightly controlled, neutral ambient temperature (31°C). To avoid stress hyperthermia (which masks the onset of fever), all injections were performed through a catheter extension. The +/+ mice responded to intravenous saline with no change in deep body temperature. To a low dose of LPS (1 µg/kg iv), they responded with a monophasic fever. To a higher dose (56 µg/kg), they responded with a polyphasic fever. Neither monophasic fever nor the first phase of polyphasic fever was attenuated in the COX-1 –/– mice, but both responses were absent in the COX-2 –/– mice. The second and third phases of polyphasic fever were also missing in the COX-2 –/– mice. The present study identifies a new, critical role for COX-2 in the mediation of the earliest responses to intravenous LPS: monophasic fever and the first phase of polyphasic fever. It also suggests that no product of the COX-1 gene, including the splice variant COX-1b (COX-3), is essential for these responses.

prostaglandin E₂; cyclooxygenase-1b; cyclooxygenase-1V₁; cyclooxygenase-3; prostaglandin H₂ synthase; body temperature; thermoregulation; febrile phases

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