Macrophage Migration Inhibitory Factor Antagonist Blocks the Development of Endometriosis In Vivo

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.

Interplay between Misplaced Müllerian-Derived Stem Cells and Peritoneal Immune Dysregulation in the Pathogenesis of Endometriosis

“…Macrophage migration inhibitory factor (MIF) activates macrophages and may therefore play a role in retaining these cells into the inflammatory sites [45]. It was demonstrated [46] that an increased secretion of MIF by peritoneal macrophages of women with endometriosis and further revealed an increased expression of this factor in eutopic endometrium and initial, active, and vascularized endometriotic lesions. Moreover, either local peritoneal fluid or systemic circulating levels of MIF were found to be higher in women with endometriosis and appeared to depend on the disease's stage and major clinical symptoms (pain and infertility) [47].…”

“…Recent data from the literature showed an important role for MIF in cell proliferation, inhibition of apoptosis [50], stimulation of metalloproteinases, and induction of angiogenesis [51]. MIF stimulates COX2 expression in ectopic endometrial cells and elicit proangiogenic and proinflammatory phenotype of macrophages, thereby potentiating their capability to stimulate the host angiogenic response and exacerbate the immunoinflammatory reaction occurring in the implantation site [46]. In addition, it was reported that macrophage migration inhibitory factor (MIF) protein secretion and mRNA expression increase significantly in endometriotic cells in response to estradiol.…”

“…It is also known that BCL2 binds to and inactivates BAX and other proapoptotic proteins, thereby inhibiting apoptosis [91]. Numerous alterations in the apoptotic intrinsic pathway, including a significant up-regulation of the antiapoptotic molecule Bcl2 and a significant downregulation of the proapoptotic factor Bax, occur in endometriosis [46]. …”

Angiogenesis and Endometriosis

“…An MIF antagonist suppressed the development of endometriotic lesions in vivo reducing the expression of VEGF, cell adhesion receptors, MMP-2, MMP-9, IL-8, and cyclooxygenase- (COX-) 2. Moreover, MIF antagonist demonstrated a proapoptotic action in the nude mouse model [84]. …”

Urine, peritoneal fluid and omental fat proteomes of reproductive age women: Endometriosis-related changes and associations with endocrine disrupting chemicals

“…In the same publication, these investigators reported that anti-MIF inhibited the ability of PF to induce proliferation of microvascular endothelial cells. Other work shows that a MIF antagonist inhibits the development of endometriosis in a nude mouse model [57]. Finally, DJ-1, which is differentially upregulated in endometriotic lesions [44], has been implicated in the pathogenesis of endometriosis by mechanisms that include modulation of the PI3/Akt pathway via PTEN [58].…”