Transactions of the Twenty-Second Annual Meeting of the Society for Maternal-Fetal Medicine
Role of tumor necrosis factor-α in the premature rupture of membranes and preterm labor pathways☆

Presented at the Twenty-second Annual Meeting of the Society for Maternal-Fetal Medicine, New Orleans, La, January 14-19, 2002.
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Abstract

Objective: To further delineate the differences between the preterm labor and premature rupture of the membrane pathways, we investigated the role of the inflammatory cytokines as activators of matrix metalloproteinases 2 and 9 in human fetal membranes. Study Design: Normal amniochorionic membrane that is maintained in an organ explant system was stimulated with interleukin-1β, tumor necrosis factor-α, or interleukin-6. The expression and activity of matrix metalloproteinases 2 and 9 in amniochorion was documented with reverse transcriptase-polymerase chain reaction and specific substrate activity assays. The matrix metalloproteinase inhibitor, tissue inhibitor of metalloproteinase-1, concentration was measured by enzyme-linked immunosorbent assay. Results: Interleukin-1β, tumor necrosis factor-α, and interleukin-6 induced the expression of matrix metalloproteinase-9 messenger RNA, whereas matrix metalloproteinase-2 expression was constitutive in control and cytokine-stimulated tissues. Matrix metalloproteinase-2 activity did not change after cytokine stimulation. Active matrix metalloproteinase-9 was significantly higher in tumor necrosis factor-stimulated tissues, which conversely were not changed after interleukin-1 or interleukin-6 stimulation. Tissue inhibitor of metalloproteinase-1 levels were decreased after interleukin-1 and tumor necrosis factor stimulation but changed after interleukin-6 stimulation. Conclusion: Only tumor necrosis factor-α increases matrix metalloproteinase-9 activity in amniochorion. (Am J Obstet Gynecol 2002;187:1159-62.)

Section snippets

Collection and culture of amniochorion

Amniochorionic membranes that were collected from women who underwent elective repeat cesarean deliveries were maintained in an organ explant system in a serum-free lactalbumin hydrolysate (0.2%, Sigma Chemical Co, St Louis, Mo)-enriched media. The details of the culture technique have been described in depth in previous publications.13, 14 At the end of 48 hours of incubation, the membranes were stimulated with recombinant human IL-1β (500 pg/mL), TNF-α (1 ng/mL), or IL-6 (250 ng/mL, all from

Results

A total of 10 cultures were analyzed for this report. RT-PCR documented the expression of MMP-2 mRNA in amniochorion-stimulated inflammatory cytokines (IL-1β, IL-6, TNF-α) and in control tissues. Stimulation with each of the three cytokines induced fetal membrane MMP-9 expression, whereas MMP-9 mRNA was absent in unstimulated tissues (Fig 1).

. RT-PCR shows constitutive expression of MMP-2 mRNA (180 bp) in cytokine-treated tissues and control tissues. MMP-9 expression (611 bp) was seen in

Comment

The MMP system is very complex with respect to production, activation, and regulation of activity. MMPs are secreted as proenzymes that require enzymatic cleavage for activation. Binding to TIMPs stoichiometrically can inhibit activated MMPs.16 Both MMP and TIMP production is regulated by a variety of stimuli that include cytokines, hormones, and tumor promoters.17

We examined the effect of the inflammatory cytokines that are thought to play a role in both PTL and PROM on MMP production and

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Reprint requests: Stephen J. Fortunato, MD, Perinatal Research Center of Women's Health Research and Education Foundation, 2300 Patterson St, Nashville, TN 37203. E-mail: [email protected]

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