Placental Cytokines and the Pathogenesis of Preeclampsia

Abstract

The authors explore the hypothesis that tumor necrosis factor-alpha (TNF-alpha) 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-alpha and interleukin-1 (IL-1), which are capable of producing endothelial cell activation and dysfunction. Hypoxia has recently been reported to increase TNF-alpha 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-alpha and IL-1 have DNA sequence 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.

Excessive stimulation of poly(ADP‐ribosyl)ation contributes to endothelial dysfunction in pre‐eclampsia

“…We know that the permeability of endothelial monolayers can be perturbed by serum from women with pre-eclampsia, and that this loss of barrier efficiency is associated with lipid peroxides and interleukin-8 (Zhang et al, 2003). These factors, in addition to plasma tumour necrosis factor alpha (Conrad & Benyo, 1997;Anim-Nyame et al, 2003), are elevated in pre-eclampsia and, as such, could be an alternative stimulus for the PARP activation observed. A direct involvement of PARP in the regulation and expression of adhesion molecules in endothelial cells has also been defined (Zingarelli et al, 1998).…”

Association of Inflammatory Cytokines, Lipid Peroxidation End Products and Nitric Oxide with the Clinical Severity and Fetal Outcome in Preeclampsia in Indian Women

“…Some researchers hypothesized that the inadequate remodeling of uterine arteries characteristic of preeclampsia is responsible for the focal ischemia and generation of pro inflammatory cytokines such as Interleukin-6 (IL-6) and tumor nrcrosis factor a (TNF-a) by the placenta [7][8][9]. IL-6 enhances endothelial cell permeability, aberrant angiogenesis and inhibits prostacyclin synthesis thereby modifying vascular physiology profoundly [10].…”

A Comparison of Circulating TNF-α in Obese and Lean Women with and without Preeclampsia

“…The resulting vasospasm, activation of the coagulation cascade and increased microvascular permeability in this syndrome lead to end organ ischemia. [3][4][5] The proinflammatory cytokine, tumor necrosis factor alpha (TNFα), produces endothelial dysfunction. 3 Through innate and acquired immune processes, TNFα modulates growth, differentiation and metabolism of many cell types, affects lipid metabolism, coagulation, insulin resistance and inflammation.…”