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

ArticleinJournal of Reproductive Immunology 77(2):142-51 · May 2008with15 Reads
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.
    • "doi:10.1371/journal.pone.0110434.g006 peritoneal macrophages [46], stimulation of endometrial cell adhesion[22], induction of angiogenic phenotype in ectopic endometrial cells [11], up-regulation of MMP activity [43]and promotion of cell survival [40,47,48]. Our current data showed that MIF genetic depletion affects ectopic endometrial tissue growth and had a significant impact on several biological pathways closely associated with the pathogenesis of endometriosis. "
    [Show abstract] [Hide abstract] ABSTRACT: Pelvic inflammation is a hallmark of endometriosis pathogenesis and a major cause of the disease's symptoms. Abnormal immune and inflammatory changes may not only contribute to endometriosis-major symptoms, but also contribute to ectopic endometrial tissue growth and endometriosis development. A major pro-inflammatory factors found elevated in peritoneal fluid of women with endometriosis and to be overexpressed in peritoneal fluid macrophages and active, highly vascularized and early stage endometriotic lesions, macrophage migration inhibitory factor (MIF) appeared to induce angiogenic and inflammatory and estrogen producing phenotypes in endometriotic cells in vitro and to be a possible therapeutic target in vivo. Using a mouse model where MIF-knock out (KO) mice received intra-peritoneal injection of endometrial tissue from MIF-KO or syngeneic wild type (WT) mice and vice versa, our current study revealed that MIF genetic depletion resulted in a marked reduction ectopic endometrial tissue growth, a disrupted tissue structure and a significant down regulation of the expression of major inflammatory (cyclooxygenease-2), cell adhesion (αv and β3 integrins), survival (B-cell lymphoma-2) and angiogenic (vascular endothelial cell growth) factorsrelevant to endometriosis pathogenesis, whereas MIF add-back to MIF-KO mice significantly restored endometriosis-like lesions number and size. Interestingly, cross-experiments revealed that MIF presence in both endometrial and peritoneal host tissues is required for ectopic endometrial tissue growth and pointed to its involvement in endometrial-peritoneal interactions. This study provides compelling evidence for the role of MIF in endometriosis development and its possible interest for a targeted treatment of endometriosis.
    Full-text · Article · Oct 2014
    • "In bladder cancer, MIF expression stimulates the proliferation of urothelial tumor cells (Guo et al., 2011). In the endometrial cancer, MIF induces VEGF thereby promoting tumor angiogenesis (Bondza et al., 2008). The high levels of MIF in prostate cancer correspond with the metastatic potential of the cancer cells (Tang et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine which plays roles in inflammation, immune responses and cancer development. It assists macrophages in carrying out functions like phagocytosis, adherence and motility. Of late, MIF is implicated in almost all stages of neoplasia and expression is a feature of most types of cancer. The presence of MIF in almost all tumors and all stages of cancer makes it an interesting candidate for cancer therapy. This review explores the roles of MIF in neoplasia.
    Full-text · Article · May 2012
    • "doi:10.1371/journal.pone.0037264.g005 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. "
    [Show abstract] [Hide abstract] 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
    Full-text · Article · May 2012
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