Decreased membrane-bound suppressor of tumorigenicity 2 (ST2) but not soluble ST2 was associated with women with recurrent pregnancy loss and recurrent implantation failure compared to controls.

Increased infiltration of immune effectors, including mast cells and natural killer cells in the mid-luteal endometrium was reported in women with recurrent pregnancy loss and repeated implantation failure. Interleukin-33 plays an important role in the cellular activation of mast cells and natural killer cells. This study investigated the endometrial IL-33/ST2 axis and its role in mast cell activation in women with RPL and RIF during the mid-luteal phase. Gene expression of ST2 was significantly decreased in RPL and RIF patients compared to normal fertile controls (Mean ± SE, 0.46 ± 0.08, 0.44 ± 0.09, 1.25 ± 0.46, P < 0.007). No differences were found in ST2/IL-33 mRNA expression ratios, IL-33, and TPSAB1 mRNA expression. Western blot analysis revealed a decreased amount of membrane-bound ST2 in RPL and RIF in the endometrium compared to controls (0.09 ± 0.02, 0.12 ± 0.08, 0.28 ± 0.07, P < 0.05). No difference was found in soluble ST2 levels. Evaluation of the ST2/IL-33 protein ratios showed no significance between groups. No differences were found in IL-33 or tryptase protein levels. A correlation analysis was performed between mRNA expression levels of IL-33, ST2, and TPSAB1 in relation to genes associated with decidualization; IL-33 was correlated with CD3E, GZMB, NCAM1, PRF1, RORC, SGK1, and TGFB1 in the RPL group and associated with CDKN2A, IL18, SLC2A1, and VEGFA in controls. Decreased amount of membrane-bound ST2 may lead to the decreased physiologic activity of IL-33 on immune cells within patients with RPL and RIF; this may lead to alterations in uNK cells contributing to immune dysregulation in the endometrium.