Macrophage migration inhibitory factor expression in the human endometrium is cycle phase-dependent and markedly increased in women having endometriosis

Abstract

Objective: Our previous studies have identified macrophage migration inhibitory factor (MIF) as one of the principal bioactive molecules involved in endothelial cell proliferation released by ectopic endometrial cells. We also found MIF to be produced locally within endometrial implants, particularly in those which are highly vascularized and representing the earliest and most active forms of the disease. This is consistent with recent data showing an important role for MIF in tumor growth-associated angiogenesis in vivo. The objective of the present study was to investigate MIF expression in the endometrial tissue of normal women throughout the menstrual cycle, and to assess whether any difference in MIF expression could be found between normal women and women suffering from endometriosis.Design: Retrospective study using frozen endometrial tissue from women with and without endometriosis.Materials/Methods: Endometrial tissue specimens were obtained from 45 women having endometriosis and 55 normal fertile women having no evidence of endometriosis at laparoscopy. MIF expression was assessed by immunohistochemistry, dual immunofluorescence, Western blot and ELISA for the protein, and by northern blot for the mRNA.Results: Immunohistochemical and dual immunofluorescence analyses showed that MIF was expressed throughout endometrial tissue, particularly in the glands, and identified endothelial cells and macrophages as cells markedly expressing MIF in the stroma. Western blot analysis showed a single 12.5 kDa band corresponding to the known molecular weight of the molecule. MIF protein and mRNA expression followed a regulated cycle phase-dependent pattern. Being elevated in the late-proliferative/early secretory phase of the menstrual cycle, MIF expression decreased in the mid-secretory phase before augmenting markedly again during the late secretory phase. Furthermore, higher expression of MIF was found in women with endometriosis as compared to normal women (p <0.0001).Conclusions: In view of its potent proinflammatory and angiogenic properties, our findings make plausible the involvement of MIF in the cyclic physiological changes occurring in the endometrial tissue during the menstrual cycle, and point toward a significant role for this factor in the pathophysiology of endometriosis.Supported by: Supported by grant MOP-37921 to Ali Akoum from The Canadian Institutes for Health Research (CIHR). A.A. is a “Chercheur-Boursier National” of the “Fonds de la Recherche en Santé du Québec (FRSQ)”. Objective: Our previous studies have identified macrophage migration inhibitory factor (MIF) as one of the principal bioactive molecules involved in endothelial cell proliferation released by ectopic endometrial cells. We also found MIF to be produced locally within endometrial implants, particularly in those which are highly vascularized and representing the earliest and most active forms of the disease. This is consistent with recent data showing an important role for MIF in tumor growth-associated angiogenesis in vivo. The objective of the present study was to investigate MIF expression in the endometrial tissue of normal women throughout the menstrual cycle, and to assess whether any difference in MIF expression could be found between normal women and women suffering from endometriosis. Design: Retrospective study using frozen endometrial tissue from women with and without endometriosis. Materials/Methods: Endometrial tissue specimens were obtained from 45 women having endometriosis and 55 normal fertile women having no evidence of endometriosis at laparoscopy. MIF expression was assessed by immunohistochemistry, dual immunofluorescence, Western blot and ELISA for the protein, and by northern blot for the mRNA. Results: Immunohistochemical and dual immunofluorescence analyses showed that MIF was expressed throughout endometrial tissue, particularly in the glands, and identified endothelial cells and macrophages as cells markedly expressing MIF in the stroma. Western blot analysis showed a single 12.5 kDa band corresponding to the known molecular weight of the molecule. MIF protein and mRNA expression followed a regulated cycle phase-dependent pattern. Being elevated in the late-proliferative/early secretory phase of the menstrual cycle, MIF expression decreased in the mid-secretory phase before augmenting markedly again during the late secretory phase. Furthermore, higher expression of MIF was found in women with endometriosis as compared to normal women (p <0.0001). Conclusions: In view of its potent proinflammatory and angiogenic properties, our findings make plausible the involvement of MIF in the cyclic physiological changes occurring in the endometrial tissue during the menstrual cycle, and point toward a significant role for this factor in the pathophysiology of endometriosis. Supported by: Supported by grant MOP-37921 to Ali Akoum from The Canadian Institutes for Health Research (CIHR). A.A. is a “Chercheur-Boursier National” of the “Fonds de la Recherche en Santé du Québec (FRSQ)”.