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TNF-Induced Apoptosis and Integrin Switching in Human Extravillous Trophoblast Cell Line¹

Department of Obstetrics and Gynecology,³ Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Department of Obstetrics and Gynecology,⁴ Kanto-Rosai Hospital, Kanagawa, Japan Department of Obstetrics and Gynecology,⁵ Saitama Medical Center, Saitama Medical School, Saitama, Japan

Differentiation of extravillous trophoblast cells (EVT) to an invasive phenotype plays an essential role in establishing and maintaining feto-placental organization during human pregnancy. A switch in integrin expression occurs during this differentiation and is accompanied by changes in the extracellular matrix (ECM). Alteration of EVT behavior is also modulated by cytokines. To investigate the molecular interactions involved in the EVT differentiation, we examined the effects of cytokines and ECM on the human EVT cell line, TCL1 cells. We found that tumor necrosis factor alpha (TNF) induced apoptosis in TCL1 cells but not in JEG3 cells derived from choriocarcinoma while the addition of interleukin-1ß, leukemia inhibitory factor, or transforming growth factor had no effect on TCL1 cells. This apoptosis was suppressed when TCL1 cells were seeded on fibronectin (Fn), collagen type I (C1), collagen type IV (C4), or laminin (Ln). Wortmannin, a specific PI3 kinase inhibitor, inhibited this suppression. Spreading assays and adhesion blocking assays indicated that TCL1 cells express integrin-5 and -6 and ß1 and ß4 subunits. Adhesion on Fn is mediated by 5ß1, and adhesion on C1, C4, or Ln is mediated by 6ß1 integrins. TNF suppressed 6 integrin expression and enhanced 1 integrin expression in a dose-dependent manner. In addition, aggregation of ß1 subunits on C4 was detected after addition of TNF. Taken together, these results suggest that TNF and ECM, through activation of PI3 kinase mediated by ß1 integrin signaling, might collaboratively regulate differentiation of trophoblast cells through integrin signaling in establishing and maintaining successful pregnancy.

¹ This work was supported in part by a grant-in-aid from the Ministry of Education (14770573, 13671727).

² Correspondence: Shingo Miyamoto, Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. FAX: 81-92-642-5414; smiya{at}gynob.med.kyushu-u.ac.jp

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