Human Placenta Constitutively Produces Interleukin-8 during Pregnancy and Enhances its Production in Intrauterine Infection1

Abstract

Interleukin-8 (IL-8) exerts unique chemotactic and activating activity on neutrophils. To address the significance of IL-8 in the fetoplacental unit during pregnancy, we cultured human placental explants that had been obtained by vaginal delivery, Caesarean section, or artificial abortion and then measured the IL-8 titer in the culture supernatants by enzyme immunoassay (EIA). Chorionic tissue from the first trimester produced a significant amount of IL-8 (2.2 +/- 0.4 ng/ml/10 mg, n = 5), while placentae in the second trimester (8.3 +/- 1.6 ng/ml/10 mg, n = 7) or at term (9.2 +/- 0.7 ng/ml/10 mg, n = 29) produced significantly higher amounts of IL-8. The presence or absence of labor did not affect the amount of placental IL-8 production. However, placentae with chorioamnionitis (25.2 +/- 1.6 ng/ml/10 mg, n = 9) showed significantly higher IL-8 production than those without chorioamnionitis (p less than 0.0001). Northern blot analysis of IL-8 mRNA expression demonstrated a constant level during pregnancy with or without chorioamnionitis, indicating the possibility that the major site of regulation of IL-8 synthesis in the placenta is posttranscriptional. Immunohistochemical analysis of first and third trimester placental tissues with rabbit anti-IL-8 antibody revealed the IL-8 producing cells to be trophoblasts and macrophage-like cells. IL-8 produced by the placental cells might contribute to potentiation of the immunocompetence of placental cells against bacteria invading the fetoplacental unit.

A Role for TLRs in the Regulation of Immune Cell Migration by First Trimester Trophoblast Cells

“…IL-8 serum concentrations in normal pregnant women were high, yet undetectable in the serum from nonpregnant women, suggesting that chemokine production is a hallmark of normal pregnancy. The high levels of IL-8 secretion by trophoblast cells, demonstrated by us and others (43), would suggest that neutrophil recruitment by trophoblast cells should also be high, since IL-8 is a potent neutrophil chemoattractant. Although neutrophil chemotaxis toward the CM from unstimulated trophoblast cells was observed, it was significantly lower than that for monocytes and NK cells.…”

“…Contrary to this hypothesis, our results suggest that the presence of innate immune cells at the implantation site may be due to chemokines produced by the trophoblast. Indeed, first trimester trophoblast cells have been demonstrated to express the chemokines SDF-1, macrophage migration inhibitory factor, IL-8, and thymus and activation-related chemokine (TARC) (41)(42)(43)(44). When the cytokine profile of unstimulated first trimester trophoblast cells was evaluated, it was notable to find the expression and secretion of a number of chemokines.…”

ATP-Binding Cassette Transporter Expression in Human Placenta as a Function of Pregnancy Condition

“…Thus, we evaluated the correlation between expression of well recognized proinflammatory cytokines, IL-8 is a potent chemotactic agent and activates neutrophils, potentiating the host defense mechanism against inflammation. It is thought to be constitutively produced by the human placenta (Shimoya et al, 1992) independent of preterm versus term delivery (Keelan et al, 1999). IL-8 is increased in placental tissue during FIG.…”

Interleukin-8 (CXCL8) stimulates trophoblast cell migration and invasion by increasing levels of matrix metalloproteinase (MMP)2 and MMP9 and integrins α5 and β1

“…It also induces angiogenesis (Koch et al 1992) and inhibits proliferation of myeloid progenitor cells (Sanchez et al 1998). Trophoblast and placental macrophages constitutively produce IL8, the concentration of which is highest at term (Shimoya et al 1992). IL8 mRNA and protein were also localized in cytotrophoblast (CT), syncytiotrophoblast, and Hofbauer cells of the placenta (Saito et al 1994).…”