RESUMEN
CONTEXT: Endometrial breakdown during menstruation and dysfunctional bleeding is triggered by the abrupt expression of matrix metalloproteinases (MMPs), including interstitial collagenase (MMP-1). The paracrine induction of MMP-1 in stromal cells via epithelium-derived IL-1alpha is repressed by ovarian steroids. However, the control by estradiol (E) and progesterone (P) of endometrial IL-1alpha expression and bioactivity remains unknown. OBJECTIVE AND DESIGN: Variations of endometrial IL-1alpha mRNA and protein along the menstrual cycle and during dysfunctional bleeding were determined using RT-PCR, in situ hybridization, and immunolabeling. The mechanism of EP control was analyzed using culture of explants, laser capture microdissection, and purified cells. Data were compared with expression changes of IL-1beta and IL-1 receptor antagonist. RESULTS: IL-1alpha is synthesized by epithelial cells throughout the cycle but E and/or P prevents its release. In contrast, endometrial stromal cells produce IL-1alpha only at menses and during irregular bleeding in areas of tissue breakdown. Stromal expression of IL-1alpha, like that of MMP-1, is repressed by P (alone or with E) but triggered by epithelium-derived IL-1alpha released upon EP withdrawal. CONCLUSIONS: Our experiments in cultured endometrium suggest that IL-1alpha released by epithelial cells triggers the production of IL-1alpha by stromal cells in a paracrine amplification loop to induce MMP-1 expression during menstruation and dysfunctional bleeding. All three steps of this amplification cascade are repressed by EP.
Asunto(s)
Endometrio/metabolismo , Epitelio/efectos de los fármacos , Hormonas Esteroides Gonadales/farmacología , Interleucina-1alfa/metabolismo , Menstruación/metabolismo , Metrorragia/metabolismo , Células del Estroma/metabolismo , Células Cultivadas , Endometrio/efectos de los fármacos , Epitelio/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Proteína Antagonista del Receptor de Interleucina 1/análisis , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/análisis , Interleucina-1alfa/genética , Interleucina-1beta/análisis , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Menstruación/genética , Metrorragia/genética , Modelos Biológicos , Técnicas de Cultivo de Órganos , Ovario/metabolismo , Comunicación Paracrina/genética , Comunicación Paracrina/fisiología , ARN Mensajero/metabolismo , Células del Estroma/efectos de los fármacosRESUMEN
CONTEXT: Cyclic remodeling and breakdown of the extracellular matrix, a unique feature of the human endometrium, depends on matrix metalloproteinases (MMPs). These enzymes are globally controlled by estradiol and progesterone or their withdrawal, but various MMPs and their tissue inhibitors (TIMPs) show distinct responses. OBJECTIVE AND DESIGN: To clarify the role of ovarian steroids in the differential regulation of MMP-1, MMP-3, MMP-7, MMP-8, MMP-10, TIMP-1, TIMP-2, and TIMP-3 mRNAs, we compared their variations in the cycling endometrium in vivo with their response to hormone addition or withdrawal in corresponding explants. RESULTS: Different patterns were identified in vivo according to the time frame (secretory vs. perimenstrual increase), sharpness (peak vs. progressive increase or decrease), and magnitude of the changes. In vivo ratios between early/midsecretory and perimenstrual phases ranged from more than 1000 (MMP-1, MMP-3, and MMP-10) to less than 10 (TIMPs). Differential response to ovarian steroids of the various MMPs and TIMPs mRNAs tested in cultured explants matched the same ranking and varied according to the phase at sampling. Remarkably, ovarian steroids repressed MMPs and TIMP-1 and TIMP-2 but, in secretory explants, increased TIMP-3 mRNA. Finally, in situ hybridization evidenced the major contribution of fibroblasts to the increase in MMP-8 mRNA at menstruation or in explants cultured without hormones. CONCLUSIONS: Both phase- and gene-specific modulators finely tune in space, time, and amplitude the global control of MMPs and TIMPs mRNAs by estradiol and progesterone in the cycling human endometrium.