Down-regulation of TIMP3 leads to increase in TACE expression and TNFα production by placental trophoblast cells.
OBJECTIVE
To determine whether down-regulation of TIMP3 expression promotes TACE expression and increases in TNFα production by placental trophoblast cells.


METHODS
Placental expression of TIMP3 and TACE was examined by immunostaining and Western blot. Effects of TIMP3 on TACE expression and TNFα production were assessed by transfection of TIMP3 siRNA into trophoblasts isolated from normal placentas. Effects of oxidative stress on trophoblast TIMP3 expression and TNFα production were also determined. Trophoblast production of TIMP3, TACE and TNFα were measured by ELISA.


RESULTS
TIMP3 expression was markedly reduced in preeclamptic placentas compared with normal placentas; oxidative stress down-regulated trophoblast TIMP3 expression and production, P < 0.01. Down-regulation of TIMP3 expression by TIMP3 siRNA resulted in significant increases in TACE expression and TNFα production, P < 0.01.


CONCLUSIONS
As TIMP3 is an endogenous TACE inhibitor, down-regulation of trophoblast TIMP3 expression/activity could result in increased TACE expression and subsequently lead to increased TNFα production in preeclamptic placentas.
Departments of Obstetrics and Gynecology, LSU Health Sciences Center, Shreveport, LA, USA; Department of Gynecology, The Third Hospital, Harbin Medical University, Harbin, China.
Rong
R
Ma
Baihan
B
Gu
Yang
Y
Gu
Lynn J
LJ
Groome
Yuping
Y
Wang
D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072198:ADAM17 Protein; D016022:Case-Control Studies; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D018384:Oxidative Stress; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
D034741:RNA, Small Interfering; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
Preeclampsia; TACE; TIMP3; TNFα; trophoblast