Differential Antipyretic Effects of Toll-Like Receptor 4 Signal Inhibitors in Male Rats.

Abstract

BACKGROUND: Pattern recognition receptors (PRR) are responsible for detecting pathogens and danger signals in organisms. Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS) and some danger-associated molecular patterns (DAMPs). Activation of this receptor initiates sickness behavior. Fever is a hallmark of this process. OBJECTIVES: We hypothesized that TLR4 signal inhibitors may have antipyretic activity. We evaluated the effect of TLR4 signal inhibitors on LPS or carrageenan-induced fever in male Wistar rats. METHODS: Core body temperature was measured via telemetric implants. Fever was induced by injection of LPS (E. coli O111:B4, 250 μg/kg, sc) or carrageenan (50 mg/kg, sc). For TLR4 signal inhibition, LPS from Rhodobacter sphaeroides (LPS-RS), IAXO-102, or naltrexone was used. Intracardiac blood samples were collected for measurement of interleukin-6 (IL-6), an endogenous pyrogen cytokine in plasma, by ELISA during the initial phase of LPS-induced fever. RESULTS: LPS-RS pretreatment (25 or 100 μg/kg, sc) did not inhibit LPS-induced fever and plasma IL-6 elevation. Other alternative TLR4 signal inhibitors, such as IAXO-102 (3 mg/kg, sc) or naltrexone (10 mg/kg, sc), also failed to abolish LPS-induced fever. An intriguing finding is that LPS-RS or naltrexone inhibited the fever caused by carrageenan. CONCLUSION: Data show that TLR4 signal inhibitors have differential antipyretic activity on fever suggesting that some alternative or complementary mechanisms might be operational for LPS-induced fever. Data also suggest that TLR4 signal inhibitors may be an alternative as a possible treatment option for DAMP-mediated clinical pathologies.