Murine Stress-triggered Abortion is Mediated by Increase of CD8+ TNF-α+ Decidual Cells via Substance P


Address reprint requests to Dr. Petra Arck, Charité, Campus Virchow Klinik, Med. Klinik/Biomedizinisches Forschungszentrum, Augustenburger Platz 1, 13353 Berlin, Germany.



PROBLEM: Stress is known to induce abortions in mice and humans. Increased levels of abortogenic type 1 helper T-cell cytokines and decreased levels of pregnancy protective cytokines could be linked to stress-triggered embryonic loss. Stress promotes neurotransmitter substance P (SP) release in tissues. SP increases the production of decidual tumor necrosis factor (TNF)-α, whereby the phenotype of these TNF-α-producing cells is hypothetical. The objective of the present study was to identify decidual TNF-α-producing cell populations that are involved in stress-induced murine abortion.
METHOD: DBA/2J-mated CBA/J female mice were exposed to ultrasonic sound stress on day 5.5 of pregnancy. The mice were randomized and half were treated with the SP NK1-receptor antagonist (SP-RA) RP 67580 (200 μg/mouse). Frequency and cytokine profile of CD8+ cells were evaluated by immunohistochemistry and flow cytometry. Degranulation of uterine mast cells was examined histologically.
RESULTS: On day 13.5 of pregnancy, the uteri were removed and the resorption rate was calculated. A mean resorption rate of 38.4% was detected in stressed mice (n=10) compared to 13.1% in non-stressed control mice (n=11, P<0.01). Injection of SP-RA decreased the abortion rate to 18.4% in stressed mice (n=19, P<0.01). Flow cytometry revealed a stress-related increase of TNF-α+/CD8+ decidual T cells, which could be abrogated by SP-RA (P<0.05). No significant differences could be observed in numbers of mast cells and total CD8+ cells in situ.
CONCLUSION: Our data suggest that stress-triggered abortion is mediated by SP, and SP receptor blockade abrogates stress-triggered abortion via reduced production of TNF-α by CD8+ T cells.