TY - JOUR
T1 - Granulysin produced by uterine natural killer cells induces apoptosis of extravillous trophoblasts in spontaneous abortion
AU - Nakashima, Akitoshi
AU - Shiozaki, Arihiro
AU - Myojo, Subaru
AU - Ito, Mika
AU - Tatematsu, Mikiko
AU - Sakai, Masatoshi
AU - Takamori, Yasushi
AU - Ogawa, Kazuyuki
AU - Nagata, Kinya
AU - Saito, Shigeru
N1 - Funding Information:
Supported by Grants-in-Aid for Scientific Research (B)–17390447 and (C)–18591797 , Grant-in-Aid for Exploratory Research 18659482 , and Grant-in-Aid for Young Scientists (B)–19791139 from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and the 21st Century COE Program.
PY - 2008/9
Y1 - 2008/9
N2 - Immune changes are known to occur in recurrent spontaneous abortion, but it is unclear whether either maternal natural killer (NK) cells or T cells attack fetus-derived trophoblasts. To clarify the immunological causes of spontaneous abortion, we examined the relationship between cytotoxic granule proteins in decidual lymphocytes, such as granulysin, granzyme B, and perforin, and the induction of apoptosis in extravillous trophoblasts (EVTs). The number of granulysin-positive CD56bright NK cells increased significantly in the decidua basalis during spontaneous abortion compared with normal pregnancy; however, granzyme B- and perforin-positive cells did not change. Interestingly, the expression of granulysin was also detected in the nuclei of EVTs in spontaneous abortion samples. When IL-2-stimulated CD56bright NK cells were cocultured with EVT cells (HTR-8/SV40neo), granulysin was found initially in the cytoplasm and then accumulated in the nuclei of the HTR-8/SV40neo cells. Furthermore, transfected cells expressing a GFP-granulysin fusion protein induced apoptosis in HTR-8/SV40neo cells independently of caspases. Our results suggest that granulysin-positive uterine NK cells attack EVTs; subsequently, the uNK-derived granulysin actively accumulates in the nuclei of EVTs, causing the death of EVTs due to apoptosis. These data support a new apoptosis pathway for trophoblasts via uNK-derived granulysin, suggesting that granulysin is involved in spontaneous abortion.
AB - Immune changes are known to occur in recurrent spontaneous abortion, but it is unclear whether either maternal natural killer (NK) cells or T cells attack fetus-derived trophoblasts. To clarify the immunological causes of spontaneous abortion, we examined the relationship between cytotoxic granule proteins in decidual lymphocytes, such as granulysin, granzyme B, and perforin, and the induction of apoptosis in extravillous trophoblasts (EVTs). The number of granulysin-positive CD56bright NK cells increased significantly in the decidua basalis during spontaneous abortion compared with normal pregnancy; however, granzyme B- and perforin-positive cells did not change. Interestingly, the expression of granulysin was also detected in the nuclei of EVTs in spontaneous abortion samples. When IL-2-stimulated CD56bright NK cells were cocultured with EVT cells (HTR-8/SV40neo), granulysin was found initially in the cytoplasm and then accumulated in the nuclei of the HTR-8/SV40neo cells. Furthermore, transfected cells expressing a GFP-granulysin fusion protein induced apoptosis in HTR-8/SV40neo cells independently of caspases. Our results suggest that granulysin-positive uterine NK cells attack EVTs; subsequently, the uNK-derived granulysin actively accumulates in the nuclei of EVTs, causing the death of EVTs due to apoptosis. These data support a new apoptosis pathway for trophoblasts via uNK-derived granulysin, suggesting that granulysin is involved in spontaneous abortion.
UR - http://www.scopus.com/inward/record.url?scp=51349159696&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2008.071169
DO - 10.2353/ajpath.2008.071169
M3 - 学術論文
C2 - 18688023
AN - SCOPUS:51349159696
SN - 0002-9440
VL - 173
SP - 653
EP - 664
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -