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Cytokine-Mediated Regulation of 92-Kilodalton Type IV Collagenase, Tissue Inhibitor of Metalloproteinase-1 (TIMP-1), and TIMP-3 Messenger Ribonucleic Acid Expression in Human Endometrial Stromal Cells¹

Department of Gynecology and Obstetrics, Stanford University Medical Center and School of Medicine (H.Y.H., Y.W., J.C.I., J.S.K., M.L.P.), Stanford, California 94305; and the Department of Obstetrics and Gynecology, Lin-Kou Medical Center, Chang Gung Memorial Hospital and University School of Medicine (H.Y.H., Y.K.S.), Taipei, Taiwan

Address all correspondence and requests for reprints to: Dr. Hong-Yuan Huang, Department of Gynecology and Obstetrics, Stanford University Medical Center and School of Medicine, Stanford, California 94305.

Interleukin-1 (IL-1) is expressed in human endometrium and has been shown to play an integral role in local cellular interactions during implantation. In addition, the matrix metalloproteinase (MMP) and its inhibitor, the tissue inhibitor of metalloproteinase (TIMP), are crucial during implantation, mediating in vitro trophoblast penetration, and are regulated by several cytokines expressed by trophoblast cells. We have investigated the roles of IL-1ß and transforming growth factor-ß (TGFß) in regulating TIMP-1, TIMP-3, and 92-kDa type IV collagenase messenger ribonucleic acid (mRNA) expression in human endometrial stromal cells using quantitative competitive PCR. Confluent stromal cell cultures treated with progesterone and estradiol for 9 days were stimulated with IL-1ß, IL-1ß plus anti-IL-1ß antibody, TGFß, and TGFß plus anti-TGFß antibody for an additional 24 h. Competitive complementary DNA fragments were constructed by deletion of a defined fragment from each of the target complementary DNA sequences and coamplified in quantitative competitive PCR as an internal standard. TIMP-1 and TIMP-3, but not 92-kDa type IV collagenase mRNA, were expressed in stromal cells. The 92-kDa type IV collagenase mRNA was only expressed after stimulation with IL-1ß. IL-1ß both augmented 92-kDa type IV collagenase mRNA expression and decreased TIMP-1 and TIMP-3 mRNA expression in a dose-dependent manner. Conversely, TGFß augmented TIMP-1 and TIMP-3 mRNA expression, but did not affect 92-kDa type IV collagenase expression. IL-1 and TGFß-mediated changes were both neutralized by specific antibodies. These results provide indirect evidence that IL-1 and TGFß may play crucial roles at the embryo-maternal interface during trophoblast invasion by regulating stromal cell expression of TIMP-1, TIMP-3, and 92-kDa type IV collagenase, all of which are known to be important in trophoblast invasion.

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