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Physiology and Pharmacology of Temperature Regulation
1Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona; and 2Section on Functional Neuroanatomy, National Institute of Mental Health, National Institutes of Health, United States Department of Health and Human Services, Bethesda, Maryland
Submitted 31 March 2005 ; accepted in final form 26 April 2005
LPS preparations cause a variety of body temperature (Tb) responses: monophasic fever, different phases of polyphasic fever, and hypothermia. Conventional (c) LPS preparations contain highly active lipoprotein contaminants (endotoxin proteins). Whereas LPS signals predominantly via the Toll-like receptor (TLR) 4, endotoxin proteins signal via TLR2. Several TLR2-dependent responses of immunocytes to cLPS in vitro are triggered by endotoxin proteins and not by LPS itself. We tested whether any Tb response to cLPS from Escherichia coli 055:B5 is triggered by non-TLR4-signaling contaminants. A decontaminated (d) LPS preparation (free of endotoxin proteins) was produced by subjecting cLPS to phenol-water reextraction. The presence of non-TLR4-signaling contaminants in cLPS (and their absence in dLPS) was confirmed by showing that cLPS (but not dLPS) induced IL-1
expression in the spleen and increased serum levels of TNF-
and IL-1 of C3H/HeJ mice; these mice bear a nonfunctional TLR4. Yet, both cLPS and dLPS caused cytokine responses in C3H/HeOuJ mice; these mice bear a fully functional TLR4. We then studied the Tb responses to cLPS and dLPS in Wistar rats preimplanted with jugular catheters. At a neutral ambient temperature (30°C), a low (0.1 µg/kg iv) dose of cLPS caused a monophasic fever, whereas a moderate (10 µg/kg iv) dose produced a polyphasic fever. In the cold (20°C), a high (500 µg/kg iv) dose of cLPS caused hypothermia. All Tb responses to dLPS were identical to those of cLPS. We conclude that all known Tb responses to LPS preparations are triggered by LPS per se and not by non-TLR4-signaling contaminants of such preparations.
body temperature; fever; hypothermia; inflammation; Toll-like receptors; TLR2; TLR4; LPS
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