IL-10 is an autocrine inhibitor of human placental cytotrophoblast MMP-9 production and invasion

During human placentation, fetal cytotrophoblast stem cells differentiate a nd then invade the uterine wall and its associated spiral arteries. This pr ocess anchors the placenta to the uterus and supplies maternal blood to the fetus. Cytotrophoblast invasion in vitro requires the expression of matrix metalloproteinase-9 (MMP-9). Recently, we showed that cytotrophoblasts pro duce interleukin-10 (IL-10), a potent immunomodulatory cytokine that could have paracrine effects on the maternal immune system. IL-10 synthesis is dr amatically downregulated after the first 12 h of culture, while MMP-9 secre tion is rapidly upregulated and the cells acquire an invasive phenotype. Th ese observations prompted us to investigate whether IL-10 is an autocrine r egulator of cytotrophoblast MMP-9 production. We found that the cells expre ssed IL-10 receptor mRNA, suggesting that autocrine effects are possible. A dding recombinant IL-10 to cytotrophoblast cultures significantly decreased the cells' MMP-9 expression at both protein and mRNA levels, but did not a ffect mRNA levels of the tissue inhibitor of metalloproteinase-3. Thus, IL- 10 may alter the proteinase/inhibitor balance. IL-10 treatment further caus ed a net decrease in MMP activity, thereby reducing cytotrophoblast invasiv eness. An antibody that neutralized endogenous IL-10 function had the oppos ite effect in all experiments. Together, these data suggest that IL-10 is a n autocrine inhibitor of cytotrophoblast MMP-9 activity and invasiveness. ( C) 1999 Academic Press.