The Transcription of Corticotropin-Releasing Hormone in Human Endometrial Cells Is Regulated by Cytokines

Abstract

Corticotropin-releasing hormone (CRH), a hypothalamic neuropeptide, is also produced in the human endometrium where it participates in local inflammatory phenomena associated with the decidualization of endometrial stroma and the implantation of the fertilized egg. The inflammatory cytokines interleukin 1 (IL-1), IL-6 and leukemia inhibitory factor (LIF) appear to be the dominant local regulators of these intrauterine inflammatory processes. In the present study we have examined the direct interactions between cytokines and CRH in the endometrium. For this purpose we have measured the effects of IL-1, IL-6 and LIF on the activity of CRH promoter inserted in human endometrial cells in culture. Homologous transient transfection experiments were conducted employing a 0.9-kb fragment of the 5' flanking region of the human CRH gene coupled to the luciferase reporter gene, using Ishikawa human endometrial cells. We have found that IL-1beta increased the activity of CRH gene promoter, in a time- and dose-dependent manner. This effect was antagonized by the IL-1 receptor antagonist IL-1ra and blocked completely by the cyclo-oxygenase inhibitor indomethacin. Similarly, IL-6 increased the activity of CRH promoter in a dose-dependent fashion, an effect partially reversed by indomethacin. LIF did not have any apparent effect. In conclusion, our data suggest that IL-1 and IL-6 exert a strong stimulatory effect on the expression of endometrial CRH. This effect is most probably mediated via prostaglandins. Based on these data we hypothesize that in the human endometrium interleukins, prostaglandins and CRH form a local network regulating the inflammatory phenomena taking place within the uterine cavity.