Kappa opioids and TGF beta 1 interact in human endometrial cells

The transforming growth factor beta 1 (TGF beta 1) is a major regulator of human endometrial function. Human endometrium possesses specific opioid bin ding sites, the majority of which belong to the kappa type, for which the p rodynorphin-derived opioids are the endogenous ligands. Since these two sys tems interact in several other tissues we postulated that opioids may affec t the production of TGF beta 1 in human endometrium. We have found that kap pa opioids exerted a time- and dose-dependent inhibitory effect on TGF beta 1 production from endometrial stromal and epithelial cells and from the Is hikawa human endometrial adenocarcinoma cell line. This effect was reversib le by the specific opioid antagonist diprenorphine. To examine if this effe ct represents a paracrine endometrial response to locally produced kappa op ioids we searched for the presence of the endogenous kappa opioid receptor ligands. Indeed, the prodynorphin transcript was detectable on Northern blo ts from normal and tumoral human endometrial cells; its size was that of th e pituitary transcript, i.e. similar to 2.4 kb long. Most immunoreactive dy norphin from human endometrium had a molecular weight of 8 kDa. Finally, im munofluorescence staining of normal and tumoral human endometrial cells rev ealed the presence of dynorphin-positive cytoplasmic secretory granules. Ta ken together, our data suggest that in human endometrium, kappa opioids and the TGF beta 1 form a paracrine network which appears to be retained by th e Ishikawa human endometrial adenocarcinoma cell line.