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 CELLS

Interleukin-1 (IL-1) is expressed in human endometrium and has been sh own to play an integral role in local cellular interactions during imp lantation. In addition, the matrix metalloproteinase (MMP) and its inh ibitor, the tissue inhibitor of metalloproteinase (TIMP), are crucial during implantation, mediating in vitro trophoblast penetration, and a re regulated by several cytokines expressed by trophoblast cells. We h ave investigated the roles of IL-1 beta and transforming growth factor -beta (TGF beta) in regulating TIMP-1, TIMP-3, and 92-kDa type IV coll agenase messenger ribonucleic acid (mRNA) expression in human endometr ial stromal cells using quantitative competitive PCR. Confluent stroma l cell cultures treated with progesterone and estradiol for 9 days wer e stimulated with IL-1 beta, IL-1 beta plus anti-IL-1 beta antibody, T GF beta, and TGF beta plus anti-TGF beta antibody for an additional 24 h. Competitive complementary DNA fragments were constructed by deleti on of a defined fragment from each of the target complementary DNA seq uences 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 TV collagenase mRNA w as only expressed after stimulation with IL-1 beta. LL-1 beta both aug mented 92-kDa type TV collagenase mRNA expression and decreased TIMP-1 and TIMP-3 mRNA expression in a dose-dependent manner. Conversely, TG F beta augmented TIMP-1 and TIMP-3 mRNA. expression, but did not affec t 92-kDa type IV collagenase expression. IL-1 and TGF beta-mediated ch anges mere both neutralized by specific antibodies. These results prov ide indirect evidence that IL-1 and TGF beta may play crucial roles at the embryo-maternal interface during trophoblast invasion by regulati ng stromal cell expression of TIMP-1, TLMP-beta, and 92-kDa type IV co llagenase, all of which are known to be important in trophoblast invas ion.