To determine whether lipopolysaccharide (LPS)-induced prostaglandin (PG) E2 production is responsible for reduced spontaneous physical activity, we measured LPS ( 1 mg/kg, i. v.)-induced changes in voluntary wheel-running activity for 24 hours in both C3H/HeJ (LPS unresponsive due to a mutation in the tlr4 gene) and C3H/HeN (LPS response) mice. We also examined the effect of tlr4-gene mutation on LPS-induced PGE2 production using peritoneal macrophages from the C3H/HeJ and C3H/HeN mice. In addition, the voluntary wheel-running activity of the C3H/HeN mice, which were injected with the PGE2 inhibitor indomethacin (IM ; 0-20 mg/kg, i. p.) 30 min before injection with or without LPS ( 1 mg/kg), was monitored for 24 hours. Wheel-running activity in the C3H/HeJ mice was maintained in spite of LPS injection, but the activity in the C3H/HeN mice was significantly reduced by LPS injection. In vitro experiment showed peritoneal macrophage PGE2 production to be lower in the C3H/HeJ mice than that in the C3H/HeN mice. IM partially, but significantly, attenuated the LPS-induced reduction in wheel-running activity in the C3H/HeN mice. Our results suggest that the transient reduction in physical activity after LPS injection is partially mediated by LPS-induced PGE2 production, and that other factors also play a role.