The involvement of inflammatory cytokines in the pathogenesis of recurrent miscarriage

• Published in: Cytokine (Philadelphia, Pa.) Vol. 58; no. 1; pp. 50 - 56
• Main Authors: Giannubilo, Stefano R., Landi, Beatrice, Pozzi, Valentina, Sartini, Davide, Cecati, Monia, Stortoni, Piergiorgio, Corradetti, Alessandra, Saccucci, Franca, Tranquilli, Andrea L., Emanuelli, Monica
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-04-2012
• Subjects: abortion (animals); Abortion, Habitual - immunology; Adult; Down-Regulation; Female; Fertility; gene expression regulation; genes; Humans; Inflammation; Interleukin-17 - metabolism; interleukin-2; Interleukin-2 Receptor alpha Subunit - metabolism; microarray technology; pathogenesis; patients; PCR array; Pregnancy; pregnant women; quantitative polymerase chain reaction; receptors; Recurrent miscarriage; statistical analysis; transforming growth factor beta 3; Transforming Growth Factor beta3 - metabolism; Trophoblast; Trophoblasts - immunology; Trophoblasts - metabolism; Up-Regulation; Recurrent miscarriage; Inflammation; Trophoblast; Fertility; PCR array
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2011.12.019

► Inflammatory cytokines are involved in unexplained recurrent miscarriage. ► The trophoblast cytokine expression pattern confirms the immunotrophic theory. ► Cytokine imbalance could be responsible for alteration of the placental environment.
To investigate the inflammatory cytokine expression pattern in trophoblastic tissue from women with unexplained recurrent miscarriage (RM).
Trophoblasts were obtained during uterine evacuation from 11 women with RM and from 20 healthy pregnant women undergoing elective termination of pregnancy, who served as controls. The array was performed using GEArray Q Series Human Inflammatory Cytokines & Receptors Gene Array HS-015 membranes. Data were confirmed by quantitative real-time PCR. The Mann–Whitney U test was performed for statistical analysis.
Microarray analysis identified three genes that were differentially expressed between RM patients and controls. We observed significant downregulation of Transforming Growth Factor beta 3 (TGF-β3) and Interleukin 25 (IL-25) (5-fold reduction and 2.5-fold reduction, respectively) and significant upregulation of CD-25, also known as Interleukin 2 receptor alpha (IL-2RA) (7-fold increase) in women with RM compared with controls.
The median ΔCt of TGF-β3 was 8.2 (interquartile range, 7.67–8.9) in RM patients vs. 5.85 (interquartile range, 5.3–6.09) in controls; the median ΔCt of IL-25 was 5.18 (interquartile range, 4.46–5.76) in RM patients vs. 3.85 (interquartile range, 3.6–4.51) in controls, and the median ΔCt of CD-25 was 9.62 (interquartile range, 7.81–12.42) in RM patients vs. 12.44 (interquartile range, 11.02–13.86) in controls.
Our results suggest that the immunological and inflammatory regulation mechanisms of the placental environment play a key role in recurrent miscarriage. The observed trophoblast cytokine expression pattern at the maternal–fetal interface confirms the immunotrophic theory, as demonstrated by a switch from a T-helper-1 (Th1) profile to a T-helper-2 (Th2) profile in women who experience recurrent miscarriages.