Responsiveness of human endometrial stromal cells to cytokines.

Cytokines are known to act in a variety of tissues, most commonly in a paracrine manner, to effect a number of biochemical processes. Previously, we found that human endometrial stromal cells respond to the action of interleukin-1 (IL-1) with an increase in the production of prostaglandins. In these investigations, we also found that IL-1 acts in endometrial stromal cells to stimulate the synthesis of IL-1 and IL-6 mRNA and protein. Specifically, in human endometrial stromal cells maintained in monolayer culture, treatment with IL-1 alpha leads to a striking increase in the synthesis of IL-1 beta mRNA and protein; this increase is IL-1 alpha-dose- and time-dependent. The pro-IL-1 beta produced, however, is not secreted into the culture medium but is retained within the stromal cell. The failure of secretion of IL-1 beta is characteristic of non-monocyte/macrophage cell types; this obtains because the enzyme that effects processing of pro-IL-1 beta (31 kDa) to the mature, secreted form of IL-1 beta (17 kDa) is believed to be present only in monocytes/macrophages. We also find that IL-1 and tumor necrosis factor-alpha (TNF-alpha) act in endometrial stromal cells to stimulate the synthesis of interleukin-6 (IL-6) mRNA and protein; the IL-6 produced by these cells is secreted into the culture medium. In addition, we find that IL-1 acts in endometrial stromal cells to inhibit the expression of mRNA for connexin43, a gap junction protein that is believed to be the principal component of gap junctions in cardiac and smooth muscle. Thus, it is likely that IL-1 action leads to a decrease in gap junction-dependent intercellular communication among endometrial stromal cells. Based on these findings, we conclude that endometrial stromal cells are responsive to the actions of IL-1 and TNF-alpha. These cells synthesize both IL-1 and IL-6; and, IL-6 is released into the extracellular medium. Thus, the possibility exists that the synthesis and action of cytokines may be involved in the mechanisms that serve to regulate the mesenchymal-epithelial interactions between endometrial stromal and glandular components; and, the formation and action of cytokines in decidua may serve to modulate immunological and infectious challenges encountered by this tissue in pregnancy.