Remodeling of uterine spiral arteries is critical for the continuation of a successful pregnancy. Uterine natural killer (uNK) cells are the predominant leukocyte population in the early pregnant decidua, and a role for these cells in spiral artery remodeling in pregnancy has been suggested. Angiogenic growth factors were measured in isolated uNK and total (unseparated) decidual cells (8–10 or 12–14 weeks gestation, n=5 each gestational age) after culture for 48 h. Angiopoietin (Ang)1, placental growth factor, transforming growth factor-β1 (TGF-β1), and vascular endothelial growth factor (VEGF)-C were measured by enzyme-linked immunosorbent assay. Angiogenin, Ang2, fibroblast growth factor basic, intercellular adhesion molecule (ICAM)-1, keratinocyte growth factor (KGF), platelet-derived growth factor-BB, and VEGF-A were measured using a FASTQuant angiogenic growth factor multiplex protein assay. Levels of Ang2, ICAM-1, and KGF, secreted by the total decidual fraction, decreased with increasing gestational age. uNK levels of Ang2 and VEGF-C also decreased with increasing gestational age. At 8–10 weeks gestation, there was no difference in the level of Ang1, Ang2, TGF-β1, and VEGF-C secreted by uNK cells and the total decidual fraction. At 12–14 weeks, uNK cells secreted significantly lower levels of VEGF-C than the total decidual fraction. Early pregnancy decidua is a major source of angiogenic growth factors whose levels decrease with increasing gestational age, suggesting that they may play a role in spiral artery remodeling. uNK cells appear to be a prominent source of Ang1, Ang2, TGF-β1, and VEGF-C within the placental bed.

A successful pregnancy requires that the maternal immune system is instructed to a state of tolerance to avoid rejection of the semiallogeneic fetal–placental unit. Although increasing evidence supports that decidual (uterine) macrophages and regulatory T cells (Tregs) are key regulators of fetal tolerance, it is not known how these tolerogenic leukocytes are induced. In this article, we show that the human fetal placenta itself, mainly through trophoblast cells, is able to induce homeostatic M2 macrophages and Tregs. Placental-derived M-CSF and IL-10 induced macrophages that shared the CD14⁺CD163⁺CD206⁺CD209⁺ phenotype of decidual macrophages and produced IL-10 and CCL18 but not IL-12 or IL-23. Placental tissue also induced the expansion of CD25^highCD127^lowFoxp3⁺ Tregs in parallel with increased IL-10 production, whereas production of IFN-γ (Th1), IL-13 (Th2), and IL-17 (Th17) was not induced. Tregs expressed the suppressive markers CTLA-4 and CD39, were functionally suppressive, and were induced, in part, by IL-10, TGF-β, and TRAIL. Placental-derived factors also limited excessive Th cell activation, as shown by decreased HLA-DR expression and reduced secretion of Th1-, Th2-, and Th17-associated cytokines. Thus, our data indicate that the fetal placenta has a central role in promoting the homeostatic environment necessary for successful pregnancy. These findings have implications for immune-mediated pregnancy complications, as well as for our general understanding of tissue-induced tolerance.

Background: This study examined whether colonoscopy or endoscopic stent insertion increases levels of carcinoembryonic antigen (CEA) and/or cytokeratin (CK) 20 mRNA expression in the peripheral circulation of patients with colorectal cancer. Methods: Peripheral venous blood samples were obtained before and after colonoscopy (38 patients) or colonic stent insertion (20). Twenty patients undergoing colonoscopy for benign conditions served as controls. Expression of mRNA was quantified using real-time reverse transcriptase–polymerase chain reaction. Results: Circulating CK20 mRNA was detected in 13 of 38 patients who had a colonoscopy and eight of 20 patients with stent insertion. CK20 mRNA expression was increased following stent insertion (P = 0·007) but not after staging colonoscopy (P = 0·454). CEA mRNA was detected in one patient who had colonoscopy and two who had a stent inserted. Neither CEA nor CK20 mRNA was found in blood samples from controls. Conclusion: Endoscopic insertion of colonic stents but not staging colonoscopy results in increased levels of CK20 mRNA in the peripheral circulation.

Increased numbers of phenotypically unusual CD56^bright CD16− uterine natural killer (uNK) cells have been associated with recurrent reproductive failure. uNK cells produce angiogenic growth factors and are potential regulators of decidual angiogenesis in early pregnancy. The final common mechanism for early pregnancy loss is thought to be early onset of the maternal circulation and excessive placental oxidative stress. We tested the hypothesis that increased uNK cells in preimplantation endometrium are associated with altered angiogenesis. Women with recurrent reproductive failure (n = 122) were investigated with uterine artery Doppler and endometrial biopsy. Immunohistochemistry was used to identify uNK, endothelial and vascular smooth muscle cells and image analysis was used to assess location, density and differentiation. uNK cell density was positively correlated with the formation of blood (P = 0.005, r = 0.5) and lymphatic vessels (P = 0.0001, r = 0.6), spiral arteriole smooth muscle differentiation (P = 0.01, r = 0.5) and endometrial oedema (P = 0.004). The functional effect of this was a reduced uterine artery resistance to blood flow. These data suggest that uNK cells may regulate angiogenesis in non-pregnant endometrium. The mechanisms of reproductive failure associated with increased uNK cell density appear to be increased angiogenesis and peri-implantation blood flow, which may lead to early maternal circulation and hence pregnancy failure due to excessive oxidative stress.