Macrophage migration inhibitory factor antagonist blocks the development of endometriosis in vivo.
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.
Endocrinologie de la Reproduction, Centre de Recherche, Hôpital Saint-François d'Assise, CHUQ, Quebec City, Québec, Canada.
Khaled
K
Khoufache
Sylvie
S
Bazin
Karine
K
Girard
Julie
J
Guillemette
Marie-Christine
MC
Roy
Jean-Pierre
JP
Verreault
Yousef
Y
Al-Abed
Warren
W
Foster
Ali
A
Akoum
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004715:Endometriosis / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006652:Histological Techniques; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology*; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000139:chemically induced*; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D017931:DNA Primers; D039564:Integrin alphaV; D039661:Integrin beta3; D016209:Interleukin-8; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D042461:Vascular Endothelial Growth Factor A; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human