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Physiology and Pharmacology of Temperature Regulation

Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se— not by lipoprotein contaminants

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 (T_b) 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 T_b 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 T_b 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 T_b responses to dLPS were identical to those of cLPS. We conclude that all known T_b 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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