Hypoxia Stimulates Cytokine Production by Villous Explants from the Human Placenta

Abstract

It has been hypothesized that inadequate placentation in the hypertensive disorder of pregnancy known as preeclampsia creates foci of placental ischemia/hypoxia leading to the elaboration of factors that compromise systemic endothelial function to produce disease sequelae. As tumor necrosis factor-alpha (TNF alpha) and interleukin-1 (IL-1) are inflammatory cytokines capable of eliciting endothelial cell dysfunction, we investigated whether the production of these inflammatory cytokines by cultured villous explants from the human placenta was affected by incubation in reduced oxygen (2% O2). The term placenta produced TNF alpha, IL-6, and low levels of IL-1alpha and IL-1beta under standard tissue culture conditions. Hypoxia significantly increased TNF alpha, IL-1alpha, and IL-1beta production by 2-, 6-, and 23-fold, respectively, but did not affect IL-6 production. Further, cytokines were immunolocalized to the syncytiotrophoblast layer as well as to some villous core cells. Hypoxic regulation of placental TNF alpha and IL-1beta production also appeared to differ based on gestational age. Finally, treatment with either cobalt chloride or an iron chelator mimicked the hypoxic response, suggesting that stimulation of placental cytokine production may involve a heme-containing, O2-sensing protein. These results suggest that placental hypoxia can lead to the elaboration of inflammatory cytokines, which may contribute to the pathophysiology of preeclampsia.

MicroRNA‐181a Regulates Local Immune Balance by Inhibiting Proliferation and Immunosuppressive Properties of Mesenchymal Stem Cells

“…The source of increasing IL-6 in maternal plasma remains unknown [73,74], but several studies found that the placenta is not the source. Our research showed that miR-181a induced expression of IL-6 in MSCs but not in trophoblast cells (data not show).…”

Invasive Cytotrophoblasts Manifest Evidence of Oxidative Stress in Preeclampsia

“…TNF-␣ is known to increase XDH/XO 26 and is increased in conditioned media from cytotrophoblast and villous explants cultured under hypoxic conditions in vitro. 27 There is also a report of increased TNF-␣ production by preeclamptic placentas. 28 If hypoxia is a stimulus, then it is perhaps not surprising that invasive cytotrophoblast, with oxygenation determined by nonanastamosing basal arteries and diffusion through several cell layers of decidua, would be affected whereas villous cytotrophoblast exposed to extensively comingled intervillous blood flow would not.…”

Endothelial Nitric Oxide Synthase Deficiency Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Mice

“…19 Whether placental hypoxia causes the high TNF-␣ in maternal plasma is less clear. 18 However, despite apparent placental hypoxia in eNOS KO(ko) pregnancies ( Figure 5), there were no significant increases in placental sFlt1 or TNF-␣ mRNA levels ( Figure 5B and 5C). Maternal plasma sFlt1 ( Figure 5A) was not elevated in pregnant eNOS KO(ko) mice, whereas it is often elevated in women with preeclampsia.…”

“…Hypoxia increases placental production of the antiangiogenic factor, sFlt1, 17 and the inflammatory cytokine, TNF-␣, 18 in human placental explants. Placental hypoxia is thought to cause the elevation in sFlt1 in maternal plasma in preeclamptic pregnancies.…”