Cyclopentenone prostaglandins (PGs) induce the synthesis of heat shock proteins (HSPs) in mammalian cells. Since arachidonic acid metabolites are implicated in the control of fever, we investigated the effect of PG treatment on thermal injury in human K562 erythro-leukemia cells. Prostaglandin A1 (PGA1) was found to protect cells after severe heat shock and to induce a thermotolerant state, which persisted for 24-48 h. Prostaglandins of the B, E, and F type were not effective. Kinetics of thermotolerance induction was comparable to heat-induced heat resistance. Establishment of a thermotolerant state was not a direct effect of PGA1, since it was dependent on de novo protein synthesis and was associated with HSP70 induction. This activity of PGA1 could be part of a protective control mechanism during fever.