Macrophage migration inhibitory factor up-regulates alpha(v)beta(3) integrin and vascular endothelial growth factor expression in endometrial adenocarcinoma cell line Ishikawa

Laboratoire d'Endocrinologie de la Reproduction, Centre de Recherche, Hôpital Saint-François d'Assise, Centre Hospitalier Universitaire de Québec, Faculté de Médecine, Université Laval, 10 rue de l'Espinay, Local D0-711, Québec G1L 3L5, Canada.
Journal of Reproductive Immunology (Impact Factor: 2.82). 05/2008; 77(2):142-51. DOI: 10.1016/j.jri.2007.07.004
Source: PubMed


Human endometrium undergoes a series of dynamic physiological changes during the menstrual cycle of reproductive age women. Many factors, including hormones, cytokines, growth factors, matrix metalloproteinases and integrins, are essential for the success of embryonic implantation into endometrial tissue. Herein, we used a well-differentiated endometrial adenocarcinoma cell line, Ishikawa, to investigate in vitro the role played by macrophage migration inhibitory factor (MIF) in the regulation of endometrial receptivity markers. Quantitative real-time polymerase chain reaction (qRT-PCR) showed that MIF induced a slight increase in alpha(v) (alphav) mRNA integrin subunit expression during the first 12h, but reached a significant difference after 24h MIF treatment compared to control, whereas beta(3) (beta3) integrin subunit displayed significant increase in mRNA 2h following treatment. Immunocytofluorescence showed strong alphav and beta3 immunostaining at 25 ng/ml MIF, and Western blotting clearly indicated increased alphav and beta3 protein expression. MIF treatment significantly stimulated vascular endothelial growth factor (VEGF) mRNA expression in a dose- and time-dependent manner after 24 h treatment. Moreover, immunocytofluorescence revealed positive VEGF immunostaining compared to control, and analysis by ELISA of VEGF release in culture supernatants demonstrated that MIF (25 ng/ml) significantly induced VEGF secretion at 12 and 24 h. In conclusion, this study provides evidence that MIF directly up-regulates alphavbeta3 integrin and VEGF expression in human endometrial Ishikawa cells and may advance our understanding of factors involved in the establishment of endometrial receptivity and successful implantation.

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    • "MIF plays an essential role in tumorigenesis, tissue remodeling and angiogenesis [26], [27], [28], [29], [30], [31], [34], [35]. Recent data from the literature and our laboratory showed an important role for MIF in cell proliferation [60], [61], inhibition of apoptosis [62], [63], [64], stimulation of metalloproteinases [65], [66] and induction of angiogenesis [30], [31], [67], [68], [69], [70]. MIF stimulates COX2 expression in ectopic endometrial cells and elicit a pro-angiogenic and pro-inflammatory phenotype [28], [37], thereby potentiating their capability to stimulate the host angiogenic response and exacerbate the immuno-inflammatory reaction occurring in the implantation site. "
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    ABSTRACT: Endometriosis, a disease of reproductive age women, is a major cause of infertility, menstrual disorders and pelvic pain. Little is known about its etiopathology, but chronic pelvic inflammation is a common feature in affected women. Beside symptomatic treatment of endometriosis-associated pain, only two main suboptimal therapeutic approaches (hormonal and invasive surgery) are generally recommended to patients and no specific targeted treatment is available. Our studies led to the detection of a marked increase in the expression of macrophage migration inhibitory factor (MIF) in the eutopic endometrium, the peripheral blood and the peritoneal fluid of women with endometriosis, and in early, vascularized and active endometriotic lesions. Herein, we developed a treatment model of endometriosis, where human endometrial tissue was first allowed to implant into the peritoneal cavity of nude mice, to assess in vivo the effect of a specific antagonist of MIF (ISO-1) on the progression of endometriosis and evaluate its efficacy as a potential therapeutic tool. Administration of ISO-1 led to a significant decline of the number, size and in situ dissemination of endometriotic lesions. We further showed that ISO-1 may act by significantly inhibiting cell adhesion, tissue remodeling, angiogenesis and inflammation as well as by altering the balance of pro- and anti-apoptotic factors. Actually, mice treatment with ISO-1 significantly reduced the expression of cell adhesion receptors αv and ß3 integrins (P<0.05), matrix metalloproteinases (MMP) 2 and 9 (P<0.05), vascular endothelial cell growth factor (VEGF) (P<0.01), interleukin 8 (IL8) (P<0.05), cyclooxygenease (COX)2 (P<0.001) and the anti-apoptotic protein Bcl2 (P<0.01), but significantly induced the expression of Bax (P<0.05), a potent pro-apoptotic protein. These data provide evidence that specific inhibition of MIF alters endometriotic tissue growth and progression in vivo and may represent a promising potential therapeutic avenue.
    Full-text · Article · May 2012 · PLoS ONE
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    • "It was recently confirmed that MIF potently stimulates nitric oxide production, which can directly mediate cell injury [68, 69] and enhance macrophage activities such as intracellular killing, phagocytosis, and H2O2 production [70]. MIF also acts as a potent angiogenic factor in autoimmune diseases [71], exerting its angiogenic effects through induction of such angiogenic mediators as vascular endothelial growth factor (VEGF) [72, 73]. "
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    ABSTRACT: Macrophage migration inhibitory factor (MIF) was originally identified in the culture medium of activated T lymphocytes as a soluble factor that inhibited the random migration of macrophages. MIF is now recognized to be a multipotent cytokine involved in the regulation of immune and inflammatory responses. Moreover, the pivotal nature of its involvement highlights the importance of MIF to the pathogenesis of various inflammatory disorders and suggests that blocking MIF may be a useful therapeutic strategy for treating these diseases. This paper discusses the function and expressional regulation of MIF in several rheumatic diseases and related conditions.
    Full-text · Article · Dec 2010
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    • "On the other hand, other studies have demonstrated that MIF promotes fibroblast migration and accelerates skin wound healing [7,8]. A close relationship between MIF and vascular endothelial growth factor (VEGF) expression has recently been reported [9,10]. "
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    ABSTRACT: To evaluate the role of macrophage migration inhibitory factor (MIF) in the wound healing process following severe chemical burns to the ocular surface. Chemical burning of the ocular surface was induced in mice (C57BL/6) via the application of 0.1 M NaOH. Macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) mRNA expression in the ocular surface and lacrimal gland was evaluated via real-time reverse transcription PCR on days 2, 7, and 30 after induction of the chemical burn. The expression of MIF protein in the ocular surface and lacrimal gland was evaluated via western blot analysis. Immunohistochemical staining was conducted to detect MIF and vasculoendothelial growth factor in the cornea during the wound healing process. The angiogenic role of MIF was further evaluated using an 8-0 polyglactin suture technique to induce corneal neovascularization. MIF, TNF-α, and IL-1β mRNA expression were elevated significantly in the ocular surface up to day 30 after chemical burn induction. TNF-α alone was elevated in the lacrimal gland. MIF protein elevation was confirmed via western blot analysis, and the spatial similarity of MIF and VEGF expression in the cornea was noted during the wound healing process. 8-0 polyglactin sutures soaked in MIF induced significantly higher numbers of new vessels on the mouse cornea after 7 days (p=0.003, Mann-Whitney test). These findings indicate that MIF performs a crucial role in wound healing on the ocular surface after the induction of chemical burns.
    Full-text · Article · Nov 2010 · Molecular vision
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