Abstract
Previously we have screened out Insulin-like Growth Factor Binding Protein 7 (IGFBP7) as a differentially expressed gene in post-implantation uterus versus pre-implantation uterus by suppressive subtractive hybridation. However its function in uterus was not clearly identified. In this research, the expression and function of IGFBP7 during post-implantation were studied. We found that IGFBP7 was mainly located in the glandular epithelium and the stroma, and was upregulated after embryo implantation. The vector pCR3.1-IGFBP7-t expressing partial IGFBP7 was constructed. Inhibition of IGFBP7 by specific DNA immunization induced significant reduction of implanted embryos and pregnancy rate. The number of implanted embryos (5.68±0.46) was significantly reduced after immunization with pCR3.1-IGFBP7-t, as compared with that of the mice immunized with the control vector (12.29±0.36) or saline (14.58±0.40) (p<0.01). After specific inhibition of IGFBP7, the T helper type 1 (Th1) cytokine IFNγ, was significantly elevated (p<0.05) and the Th2 cytokines IL-4 and IL-10, were reduced in uteri (p<0.05). The increase of Tbet and the decrease of Gata3 were found in mice peripheral lymphocytes by flow cytometry. The expression of decidualization marker IGFBP1 and angiogenesis regulator VEGF were declined in uteri (p<0.05). The expression of apoptosis-associated proteins, caspase3 and Bcl-2, were also declined (p<0.05). These results showed that inhibition of IGFBP7 induced pregnancy failure by shifting uterine cytokines to Th1 type dominance and repressing uterine decidualization.
Highlights
Insulin-like Growth Factor Binding Protein 7 (IGFBP7) is a 31-kD secretory protein that is known as IGFBP-related protein 1 (IGFBP-rP1), mac25, TAF or angiomodulin [1]
The expression of the IGFBP7-t recombinant protein was confirmed by the specific reaction of the antisera from the mice immunized with pCR3.1-IGFBP7-t and the Hela cells transfected with pCR3.1-IGFBP7-t (Fig. 2A a)
No positive signal was detected for the Hela cells transfected with pCR3.1-IGFBP7-t when the antisera from the mice immunized with pCR3.1 or saline were used (Fig. 2A b and c)
Summary
IGFBP7 is a 31-kD secretory protein that is known as IGFBP-related protein 1 (IGFBP-rP1), mac, TAF or angiomodulin [1]. IGFBP7 is widely known as a tumor suppressor gene and is mostly downregulated in many types of cancers [4,5,6,7]. IGFBP7 mRNA is found in uterine glandular epithelial cells and endometrial stromal cells (ESCs), and the mRNA expression is elevated from the mid to late secretory phase of the menstrual cycle in women [8]. In vitro studies have revealed that IGFBP7 functions as a decidualization modulator in endometrial stromal cells [9,10]. In human umbilical vein endothelial cells, IGFBP7 treatment suppressed extrinsic VEGFinduced tube formation, proliferation, and the phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) 1/2 [11]
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