Deborah Fairchild Benyo

Placental Cytokines and the Pathogenesis of Preeclampsia

The authors explore the hypothesis that tumor necrosis factor‐α (TNF‐α) and possibly other inflammatory cytokines are overproduced by the placenta in response to local ischemia/hypoxia contributing to increased plasma levels, and subsequent endothelial activation and dysfunction in the pregnancy disorder, preeclampsia. It is widely held that inadequate trophoblast invasion and physiologic remodeling of spiral arteries initiate placental ischemia/hypoxia in preeclampsia. Furthermore, focal areas of placental hypoxia have been implicated in the production of “toxic” factor(s) by the placenta, which circulate and cause maternal disease. Placental trophoblast cells and fetoplacental macrophages normally produce TNF‐α and in‐terleukin‐1 (IL‐1), which are capable of producing endothelial cell activation and dysfunction. Hypoxia has recently been reported to increase TNF‐α and IL‐1 production by term villous explants from the human placenta. Placental cells also express erythropoietin (EPO), which is the prototype molecule for transcriptional regulation by hypoxia in mammals. Interestingly, TNF‐α and IL‐1 have DNA sequences homologous or nearly homologous to the hypoxia‐responsive enhancer element of the EPO gene, thus providing a potential, but as of yet, untested molecular link between placental hypoxia and stimulation of cytokine production. Inflammatory cytokines overproduced by the placenta in response to hypoxia may then lead to increased plasma levels and endothelial activation and dysfunction in preeclampsia. The purpose of this short review is to critically evaluate the hypothesis that placental cytokines contribute to the pathogenesis of preeclampsia. Of note, the etiology of the disease presumably related to deficient trophoblast invasion is beyond the scope of this work.

Circulating Levels of Immunoreactive Cytokines in Women with Preeclampsia

PROBLEM: Circulating inflammatory cytokines have been implicated in the pathogenesis of preeclampsia. To test this hypothesis, we measured plasma levels of immunoreactive tumor necrosis factor (TNF)‐α and ‐β, interleukin (IL)−1α and ‐β, and IL‐6 and −10 in women with preeclampsia, in women with transient gestational hypertension, and throughout normal pregnancy.

Expression of erythropoietin by the human placenta.

Circulating levels of maternal erythro‐poietin (EPO) rise during gestation due to increased biosynthesis of the hormone. Our objective was to investigate the human placenta as a potential extrarenal site of EPO production. Using two mono‐clonal antibodies recognizing different antigenic determinants, we identified immunoreactive EPO associated with villous cytotrophoblast, endovascular and intravascular cytotrophoblast, cytotrophoblast cell columns, and syncytiotrophoblast of first and second‐trimester placenta as well as syncytiotro‐ phoblast and extravillous cytotrophoblast of normal third‐trimester and preeclamptic placenta. In addi‐tion, cultured JAR (trophoblast‐derived) choriocar‐cinoma cells, cytotrophoblasts isolated from term placenta, villous core cells, and possibly other non‐ trophoblast cells within the decidual basal plate ex‐pressed immunoreactive EPO. Using reverse transcription‐polymerase chain reaction and EPO‐ specific primers, a 378 bp DNA product was ampli‐fied from placental tissues of various gestational ages, cytotrophoblasts isolated from term placenta, and JAR choriocarcinoma cells. The amplified product yielded restriction enzyme fragments of predicted sizes. On Southern analysis, hybridization was observed for two of these fragments in which the radiolabeled EPO cDNA probe did not overlap with the primer sequences. Finally, the JAR choriocarcinoma cells elaborated EPO into the culture medium as determined by enzyme‐linked immunosorbant assay and expressed EPO mRNA as determined by Northern analysis, both of which were stimulated by hypoxia (15‐20 torr). Taken together, these results suggest a new site of EPO expression: the trophoblast cell of the human placenta.—Conrad, K. P., Benyo, D. F., Westerhausen‐Larsen, A., Miles, T. M. Expression of erythropoietin by the human placenta. FASEB J. 10, 760‐766 (1996)