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

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.