Wang Z, Liu M, Nie X, Zhang Y, Chen Y, Zhu L, Chen X, Chen L, Chen H, Zhang J
The Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Department of Gynecology and Obstetrics, People's Republic of China.
The Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Department of Gynecology and Obstetrics, People's Republic of China.
Placenta. 2015 Jun;36(6):652-60. doi: 10.1016/j.placenta.2015.03.004. Epub 2015 Mar 12.
Nucleotide binding and oligomerization leucine-rich repeats (NLR) are recognized as members of pattern-recognition receptors that play important roles in host innate immune defenses. In this study, we have investigated the expression and regulation of nucleotide-binding oligomerization domains 1 and 2 (NOD1 and NOD2) on the invasiveness of primary human trophoblasts during the first trimester of pregnancy.
The expression of NOD1 and NOD2 by human first rimester villi from recurrent spontaneous abortion (RSA) patients and normal pregnancy was analyzed by immunochemistry, western blot and real-time RT-PCR, respectively. The effects of ligands on the regulation of their receptors and invasiveness of trophoblasts were examined. The ELISA was used to measure the secretion of matrix matallopeptidase-9 (MMP9) and matrix matallopeptidase-2 (MMP2) by trophoblasts. We also investigated the signaling pathways involved in invasion of trophoblasts.
The higher NOD1 and NOD2 were observed in villi from patients who experienced RSA compared with those who experienced a normal pregnancy. The ligands can up-regulate the expression of their receptors. After activation, NOD1 and NOD2 inhibited the invasion of trophoblast cells by decreasing MMP9 but not MMP2. After the activation of NOD1 and NOD2, the mitogen-activated protein kinase (MAPK)/p38 pathway was activated time dependently. Blocking this pathway with a specific inhibitor (SB203580) attenuated NOD1-and NOD2-regulated trophoblast invasions.
These results suggest that abnormal elevated NOD1 and NOD2 expression in villi relate to pregnancy outcomes. Further, activation of NOD1 and NOD2 could have a bearing on our understanding of the invasive ability of trophoblasts.
核苷酸结合寡聚化富含亮氨酸重复序列（NLR）被认为是模式识别受体的成员，在宿主先天免疫防御中发挥重要作用。在本研究中，我们调查了核苷酸结合寡聚化结构域1和2（NOD1和NOD2）在妊娠早期对人原代滋养层细胞侵袭性的表达和调控。
分别通过免疫化学、蛋白质印迹和实时逆转录聚合酶链反应分析复发性自然流产（RSA）患者和正常妊娠的人孕早期绒毛中NOD1和NOD2的表达。检测配体对其受体调控及滋养层细胞侵袭性的影响。采用酶联免疫吸附测定法检测滋养层细胞分泌基质金属蛋白酶-9（MMP9）和基质金属蛋白酶-2（MMP2）的情况。我们还研究了参与滋养层细胞侵袭的信号通路。
与正常妊娠患者相比，RSA患者绒毛中NOD1和NOD2的表达更高。配体可上调其受体的表达。激活后，NOD1和NOD2通过降低MMP9而非MMP2来抑制滋养层细胞的侵袭。NOD1和NOD2激活后，丝裂原活化蛋白激酶（MAPK）/p38通路呈时间依赖性激活。用特异性抑制剂（SB203580）阻断该通路可减弱NOD1和NOD2调控的滋养层细胞侵袭。
这些结果表明，绒毛中NOD1和NOD2表达异常升高与妊娠结局有关。此外，NOD1和NOD2的激活可能有助于我们理解滋养层细胞的侵袭能力。
