Inhibition of Macrophage Migration Inhibitory Factor Reduces Endometriotic Implant Size in Mice with Experimentally Induced Disease

Abstract

Aim Macrophage migration inhibitory factor (MIF) is a cytokine whose expression is elevated in endometriotic tissue from women with the disease but the functional role of this factor in the pathogenesis of the disease is uncertain. The objective of the current study was to examine the role of MIF in the pathogenesis of endometriosis. Method Experimental endometriosis was induced in mice and the ability of the MIF antagonist, ISO-1, to reduce endometriotic implant size was assessed. Results Administration of ISO-1 resulted in a significant reduction in implant size and vascularity (as assessed by Flk1 mRNA expression) which was not associated with an alteration in the reproductive cycle. Conclusion These data suggest that inhibition of MIF activity is associated with a significant reduction in endometriotic implant size and leads us to speculate that a similar approach of targeting MIF may prove useful in treating endometriosis in humans.

Dissecting the miR-451a-Mif Pathway in Endometriosis Pathophysiology Using a Syngeneic Mouse Model: Temporal Expression of Lesion Mif Receptors, Cd74 and Cxcr4

“…Experimental mouse models are essential for enhancing our understanding on endometriosis pathophysiology [ 5 ]. The mouse model which we initially described in 2011 [ 6 ] consists of using PMSG-primed endometrial tissue from immature, immune competent, reproductively intact donors. Using this model, physiological levels of endogenous E2 are liberated which aids in the establishment of ectopic lesions (endometrial tissue from either unstimulated or PMSG + hCG, the latter in which progesterone levels are elevated, do not establish ectopically).…”

“…Experimental mouse models are essential for enhancing our understanding on endometriosis pathophysiology [5]. The mouse model which we initially described in 2011 [6] consists of using PMSG-primed endometrial tissue from immature, immune competent, In contrast to Cd74, Cxcr4 mRNA expression (Figure 3) slightly increased at 1 week from induction (1.43-fold increase, p = 0.093) with minimal increase (p < 0.05) from weeks 2-and 4-weeks post-endometriosis induction (week 0) in mice with WT lesions. However, at week 8, Cxcr4 expression was significantly less compared to all other time points (p < 0.05; Figure 3).…”

“…Experimental mouse models are essential for enhancing our understanding on endometriosis pathophysiology [5]. The mouse model which we initially described in 2011 [6] consists of using PMSG-primed endometrial tissue from immature, immune competent, Compared to WT lesions, lesions developed from miR-451a deficient tissue exhibited a significant increase at 1-week post-induction and this increase remained significantly elevated through week 8 post-induction. In comparison to Cd74 levels, Cxcr4 levels were approximately 30-fold less abundant in lesion tissue from WT mice and 180-fold less abundant in lesions derived from miR-451a deficient tissue.…”

“…Administration of exogenous estrogen/estradiol (E2) to the host, often used to promote lesion establishment and survival should ideally be avoided to prevent masking or confounding of study endpoints. With this in mind, we developed one of the first immune competent, reproductively intact mouse models for endometriosis study that avoided administration of exogenous E2 to host mice [ 6 ]. Figure 1 depicts the general procedure for induction of experimental disease based upon this concept.…”

“…In addition, MIF is predominantly expressed in glandular epithelial cells of both eutopic endometrium [ 26 , 27 ] and robustly expressed in epithelium of active and early/stage I endometriotic lesions [ 27 ] with focal stromal staining in both tissue types. Two independent studies [ 6 , 28 ] utilized experimental mouse models for endometriosis to demonstrate that Mif plays an active role in endometriosis pathophysiology as administration of the MIF antagonist, ISO-1, reduced endometriotic lesion size.…”