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Tumor Necrosis Factor— Converting Enzyme in the Human Placenta Throughout Gestation

Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan, College of Medicine, Chang Gung University, Tao-yuan, Taiwan

Szu-Fu Chen, MD, PhD

Department of Physical Medicine and Rehabilitation, Cheng Hsin Medical Center, Taipei, Taiwan

Ching-Chang Hsieh, MD

Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan, College of Medicine, Chang Gung University, Tao-yuan, Taiwan

Jenn-Jeih Hsu, MD

Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan, College of Medicine, Chang Gung University, Tao-yuan, Taiwan

Meng-Jen Li, BA

Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan

Yi-Lin Yeh, MS

Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan

T'sang-T'ang Hsieh, MD

Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan, tth3388{at}adm.cgmh.org.tw, College of Medicine, Chang Gung University, Tao-yuan, Taiwan

Ectodomain shedding of epidermal growth factor receptor ligands such as transforming growth factor— (TGF-), heparin-binding epidermal growth factor—like growth factor (HBEGF), and amphiregulin (AREG) is considered to be important during implantation. Tumor necrosis factor— converting enzyme (TACE) has been suggested as the major sheddase for these molecules. The objectives of this study are (1) to characterize the expression of TACE in the human placenta throughout gestation; (2) to determine the association between the expression of TACE with TGF-, HBEGF, and AREG; (3) to ascertain whether TACE mediates TGF-, HBEGF, and AREG shedding; and (4) to examine the effect of hypoxia on the expression of TACE. By analyzing a total of 55 villous samples representing different gestational ages, the authors found that TACE was continuously expressed in the placentas throughout gestation and that the levels of TACE were positively correlated with the levels of TGF-, HBEGF, and AREG. Preadministration of a TACE inhibitor in villous explant cultures or transfection of cytotrophoblastic cells with TACE-specific small interference RNA decreased the shedding of HBEGF and AREG. Moreover, hypoxia (2% O₂) caused an increase in the levels of TACE mRNA and protein in villous explants and primary cytotrophoblastic cells in vitro. These results indicate that oxygen regulates the expression of TACE and that TACE may be important for placental development during human pregnancy.

Key Words: Placenta • transforming growth factor- • heparin-binding epidermal growth factor—like growth factor • amphiregulin • tumor necrosis factor— converting enzyme.

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