Although the involvement of blood-borne PGE₂ in fever has been hypothesized by several authors and has substantial experimental support, the current literature often rejects this hypothesis because several attempts to induce fever by a peripheral PGE₂ failed. However, it is usually ignored that the amphipathic molecules of PGE₂ are readily self-associating and that such an aggregation could have prevented the peripherally administered PGE₂ (free form) from expressing its pyrogenic activity, thus leading to false negative results. To ensure disaggregation of PGE₂, we prepared its complex within a carrier protein, human serum albumin (HSA). HSA was purified with activated charcoal and polymixin B-polyacrylamide gel and incubated with PGE₂ for 1 h at 37°C. Adult Chinchilla rabbits were injected intravenously with PGE₂-HSA complex in either the higher (75 µg/kg PGE₂:30 mg/kg HSA) or the lower (15 µg/kg:6 mg/kg) dose, and the rectal temperature (T_r) was measured. In the controls, either the ligand alone or the carrier alone was administered. At the higher dose, neither free PGE₂ nor albumin alone was pyrogenic, whereas the PGE₂-HSA complex produced a fever characterized by a short latency (<10 min) and a maximal T_r rise of 0.7 ± 0.2°C. At the lower dose, none of the substances affected the T_r. This study demonstrates a marked pyrogenic activity of the intravenous PGE₂-HSA, but not of the free PGE₂. Administration of a preformed complex may be more physiologically relevant than administration of the free ligand because of the ligand's disaggregation, protection from enzymatic degradation, and facilitated delivery to targets. Our study supports the hypothesis that peripheral PGE₂ is involved in fever genesis.

prostanoids; carrier-mediated transport; febrile response; temperature regulation; neuroimmunomodulation; rabbits

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