Granzymes D, E, F, and G are regulated through pregnancy and by IL-2 and IL-15 in granulated metrial gland cells.

Granulated metrial gland (GMG) cells are NK cells that proliferate and differentiate within the murine uterus during pregnancy. They have been predicted to play important roles in nurturing the embryo, normal placentation, and uterine tissue remodeling. GMG cell differentiation is manifested by the accumulation of the cytolytic mediators, perforin, granzyme A, and granzyme B, within cytoplasmic granules. The signaling mechanisms required for GMG cell differentiation are largely unknown, although recent in vitro assays have implicated IL-15 in these events. In this report, we demonstrate that granzymes D, E, F, and G (granzymes D-G) are also expressed in GMG cells but at a later stage in pregnancy when compared with granzyme A expression. Whereas granzyme A is expressed in early to mid-gestation, the expression of granzymes D-G peak in mid- to late gestation. In addition, we show that the expression patterns of IL-2Rbeta and the IL-2Rgamma mRNAs overlap with that of granzyme D-G mRNAs in the pregnant uterus. Finally, we demonstrate that granzymes D-G are up-regulated by IL-2 and IL-15 in primary cultures containing GMG cells. Taken together, these results suggest that IL-2 and/or IL-15 may regulate GMG cell differentiation in vivo, and that granzymes D-G may have different functions than granzyme A during pregnancy.