Submitted April 15, 2002
Returned for revision May 2, 2002
Accepted October 23, 2002
Female Reproductive Tract
Differential Regulation of the Expression of Matrix
Metalloproteinases and Tissue Inhibitors of
Metalloproteinases by Cytokines and Growth Factors in
Bovine Endometrial Stromal Cells and Trophoblast Cell Line
BT-1 In Vitro
Michiko Hirata 1,
Takashi Sato 1*,
Michiko Tsumagari 1,
Arata Shimada 2,
Haruo Nakano 2,
Kazuyoshi Hashizume 2,
Akira Ito 1
1 Tokyo University of Pharmacy and Life Science
2 National Institute of Agrobiological Sciences
* To whom correspondence should be addressed. E-mail: satotak{at}ps.toyaku.ac.jp.
Abstract
Degradation and reconstitution of extracellular matrix in
uterine endometrium is a crucial event for embryonic
implantation, and is regulated by matrix
metalloproteinases (MMPs) and tissue inhibitors of
metalloproteinases (TIMPs). In the present study, we
investigated the regulation of MMP and TIMP expression in
cultured bovine endometrial stromal cells and a bovine
trophoblast cell line BT-1 (BT-1 cells). The production of
proMMP-9 was induced by transforming growth factor 
(TGF-) and 12-O-tetradecanoylphorbol
13-acetate in the stromal cells. The treatment of BESCs
with TGF-, insulin-like growth factor-I (IGF-I) and
hepatocyte growth factor (HGF) resulted in a significant
increase in the level of TIMP-1 in the culture medium. In
addition, a significant increase of TIMP-2 production was
observed in interleukin (IL)-1
and HGF-treated
BESCs. However, the expression of TIMPs-1 and -2 mRNA was
not augmented by these factors. The treatment of BESCs
with 12-O-tetradecanoylphorbol 13-acetate resulted
in a significant increase in the level of TIMP-1 but a
significant decrease in the level of TIMP-2 in the stromal
cells. Membrane type 1-MMP mRNA expression in the stromal
cells was augmented by tumor necrosis factor
(TNF-), IL-6, HGF and
12-O-tetradecanoylphorbol 13-acetate. On the other
hand, BT-1 cells constitutively produced proMMP-9 and
proMMP-2, and the treatment of BT-1 cells with
TNF-, HGF and 12-O-tetradecanoylphorbol
13-acetate resulted in a significant increase in the level
of proMMP-9, but not proMMP-2. The production of TIMP-1 in
BT-1 cells was also augmented by IL-1,
TNF-, and HGF at the level of translation, and was
transcriptionally increased by
12-O-tetradecanoylphorbol 13-acetate. However, the
level of TIMP-2 mRNA in BT-1 cells was not affected by any
of the treatments. These results suggest that the
expression of MMPs and TIMPs is differently regulated by
cytokines and growth factors, and the production of TIMP-1
and TIMP-2 may not be accompanied by changes in their mRNA
expression in bovine endometrium and trophoblasts.
Furthermore, as in the case of humans and rodents, MMPs
and TIMPs may contribute to the control of degradation and
reconstitution of extracellular matrix in bovine
endometrium during embryonic implantation and early
placentation.
Key words:
Cytokines •
Growth factors •
Implantation •
Placenta •
Trophoblast
