A P1 clone containing the gene for human glutathione dependent PGE synthase (PGES) was isolated and characterized. The gene is divided into three exons, spans 14.8 kb and was localized to chromosome 9q34. 3. In A549 cells, the protein and activity levels of PGES were increased by interleukin-1beta. This increase was prevented by phenobarbital. Reporter constructs containing the 5'-flanking region of exon 1, which exhibited strong promoter activity, responded accordingly, except that interleukin-1beta induced a transient increase followed by a decrease. As cyclooxygenase 2 expression has been reported to respond in a similar fashion, a transcriptional regulatory basis for the observed co-regulation with PGES is implied. The strong down-regulation by phenobarbital raises important issues concerning its mechanisms of action.