Physiological significance of placental leucine aminopeptidase /oxytocinase at the interface between mother and fetus

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We firstly demonstrated that the region from-297 to-94, which contains four footprint sites (FP1 to FP4), is important for transcription in choriocarcinoma trophoblastic cells. AP-2α, AP-2γ, and Ikaros binding to FP3 (-214 to -183) was important for high promoter activity in these cells. Functional analysis showed that AP-2 is critical for human P-LAP gene expression and Ikaros cooperates with AP-2 to induce maximal promoter activity. This is apparently the first result that Ikaros, initially characterized as a lymphoid-restricted transcriptional factor, is expressed in trophoblasts. P-LAP promoter region contains putative binding sites for cytokine-induced transcription factors. We therefore postulated that inflammatory cytokines suppress P-LAP expression in trophoblasts. Interleukin-1beta (IL-1β) increased P-LAP activity and proteins. Semi-quantitative RT-PCR and Southern blotting showed that IL-1β also increased P-LAP mRNA, which was abrogated by prior exposure to cycloheximide. Luciferase assays did not reveal any regulatory regions that could explain IL-1β-induced P-LAP mRNA accumulation. Immunohistochemical analysis of the human placenta with chorioamnionitis demonstrated prominent P-LAP staining at sites of abundant inflammatory cell infiltration. These findings indicated that prolonged exposure to IL-1β induces P-LAP in the placenta, possibly via other de novo protein synthesis. Transmission immunoelectron microscopy revealed that P-LAP was expressed on the surface of apical microvilli of syncytiotrophoblast cells. Our observation that P-LAP is present on the microvilli, which is a site of interaction between the mother and fetus, suggests possible involvement of these enzymes in cleaving peptide hormones from the fetus and mother in order to regulate bioactivity.