Infection and Immunity, April 1999, p. 1539-1546, Vol. 67, No. 4
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Division of Pulmonary and Critical Care
Medicine1 and Division of Infectious
Disease,6 Department of Medicine,
Received 20 July 1998/Returned for modification 5 October
1998/Accepted 25 November 1998
Fever improves survival in acute infections, but the effects of
increased core temperature on host defenses are poorly understood. Tumor necrosis factor alpha (TNF-
) is an early activator of host defenses and a major endogenous pyrogen. TNF-
expression is
essential for survival in bacterial infections but, if disregulated,
can cause tissue injury. In this study, we show that passively
increasing core temperature in mice from the basal (36.5 to 37.5°C)
to the febrile (39.5 to 40°C) range modifies systemic TNF-
expression in response to bacterial endotoxin (lipopolysaccharide). The
early TNF-
secretion rate is enhanced, but the duration of maximal TNF-
production is shortened. We identified Kupffer cells as the
predominant source of the excess TNF-
production in the warmer animals. The enhanced early TNF-
production observed at the higher temperature in vivo could not be demonstrated in isolated Kupffer cells
or in precision-cut liver slices in vitro, indicating the participation
of indirect pathways. Therefore, expression of the endogenous pyrogen
TNF-
is regulated by increments in core temperature during fever,
generating an enhanced early, self-limited TNF-
pulse.
*
Corresponding author. Mailing address: 10 N. Greene
St., Rm. 3D127, Baltimore, MD 21201. Phone: 410-605-7197. Fax:
410-605-7915. E-mail: jhasday{at}umaryland.edu.
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