The transcription of corticotropin-releasing hormone in human endometrial cells is regulated by cytokines

Corticotropin-releasing hormone (CRH), a hypothalamic neuropeptide, is also produced in the human endometrium where it participates in local inflammat ory phenomena associated with the decidualization of endometrial stroma and the implantation of the fertilized egg, The inflammatory cytokines interle ukin 1 (IL-1), IL-6 and leukemia inhibitory factor (LIF) appear to be the d ominant local regulators of these intrauterine inflammatory processes. In t he present study we have examined the direct interactions between cytokines a nd 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 en dometrial cells in culture. Homologous transient transfection experiments w ere 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 huma n endometrial cells. We have found that IL-1 beta increased the activity of CRH gene promoter, in a time- and dose-dependent manner. This effect was a ntagonized by the IL-1 receptor antagonist IL-1 ra and blocked completely b y 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 conclusi on, our data suggest that IL-1 and IL-6 exert a strong stimulatory effect o n the expression of endometrial CRH. This effect is most probably mediated via prostaglandins. Based on these data we hypothesize that in the human en dometrium interleukins, prostaglandins and CRH form a local network regulat ing the inflammatory phenomena taking place within the uterine cavity. Copy right (C) 1999 S.Karger AG, Basel.