MIF May Participate in Pathogenesis of Polycystic Ovary Syndrome in Rats through MAPK Signalling Pathway

Abstract

The polycystic ovary syndrome (PCOS) model was established in rats and correlation between the expression of macrophage migration inhibitory factor (MIF) and cytokinesis with the MAPK signalling pathway in the rat ovary was measured. The PCOS model in rats was established by dehydroepiandrosterone (DHEA). Thirty sexually immature female Sprague-Dawley rats were randomly and equally assigned to three groups: control group, PCOS group, and PCOS with high-fat diet (HFD) group. Serum hormones were assayed by radioimmunoassay (RIA). The ovaries were immunohistochemically stained with MIF, and the expression of MIF, p-JNK and p-p38 was detected by Western blotting in ovaries. The serum testosterone level, LH concentration, LH/FSH ratio, fasting insulin level and HOMA IR index in the PCOS group (6.077±0.478, 13.809±1.701, 1.820±0.404, 10.83±1.123 and 1.8692±0.1096) and PCOS with HFD group (6.075±0.439, 14.075±1.927, 1.779±0.277, 10.20±1.377 and 1.7736±0.6851) were significantly higher than those in the control group (4.949±0.337, 2.458±0.509, 1.239±0.038, 9.53±0.548 and 1.5329±0.7363), but there was no significant difference between the PCOS group and PCOS with HFD group. The expression levels of MIF, p-JNK, and p-p38 in the PCOS group (0.4048±0.013, 0.6233±0.093 and 0.7987±0.061) and PCOS with HFD group (0.1929±0.012, 0.3346±0.103 and 0.3468±0.031) were obviously higher than those in control group (0.2492±0.013, 0.3271±0.093 and 0.3393±0.061), but no significant difference was observed between PCOS group and PCOS with HFD group. It was suggested that MIF may participate in the pathogenesis of PCOS through the MAPK signalling pathway in PCOS rats induced by DHEA.

Keywords

polycystic ovary syndrome / high-fat diet / dehydroepiandrosterone / migration inhibitory factor / MAPK signalling pathway / rats

References

[1] MorrisonMC, KleemannR. Role of macrophage migration inhibitory factor in obesity, insulin resistance, type 2 diabetes, and associated hepatic comorbidities: a comprehensive review of human and rodent studies. Front Immunol, 2015, 6: 308

[2] ZabulieneL, TutkuvieneJ. Body composition and polycystic ovary syndrome. Medicina (Kaunas, Lithuania), 2010, 46(2): 142

[3] SeliE, DulebaAJ. Optimizing ovulation induction in women with polycystic ovary syndrome. Curr Opin Obstet Gynecol, 2002, 14(3): 245-254

[4] GonzálezF, KirwanJ, RoteN, et al.. Glucose and lipopolysaccharide regulate proatherogenic cytokine release from mononuclear cells in polycystic ovary syndrome. J Reprod Immunol, 2014, 103(6): 38-44

[5] PhelanN O, ConnorA, TunTK, et al.. Leucocytosis in women with polycystic ovary syndrome (PCOS) is incompletely explained by obesity and insulin resistance. Clin Endocrinol, 2012, 78(1): 107-113

[6] HyejinL, Jee-YoungO, Yeon-AhS, et al.. Is insulin resistance an intrinsic defect in asian polycystic ovary syndrome. Yonsei Med J, 2013, 54(3): 609-614

[7] Un JuJ, Myung-SookC. Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease. Int J Mol Sci, 2014, 15(4): 6184-6223

[8] BennettB, BloomBR. Studies on the migration inhibitory factor associated with delayed-type hypersensivity: cytodynamics and specificity. Transplantation, 1967, 5(4): 996-1000

[9] JaveedA, ZhaoY. Macrophage-migration inhibitory factor: role in inflammatory diseases and graft rejection. Inflamm Res, 2008, 57(2): 45-50

[10] HirokiM, WataruI, KazunoriT, et al.. Augmented reduction of islet β-cell mass in Goto-Kakizaki rats fed high-fat diet and its suppression by pitavastatin treatment. J Diabetes Investig, 2012, 3(3): 235-244

[11] KleemannR, KapurniotuA, FrankRW, et al.. Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase. J Mol Biol, 1998, 280(1): 85-102

[12] TerrazasCA, HuitronE, VazquezA, et al.. MIF synergizes with Trypanosoma cruzi antigens to promote efficient dendritic cell maturation and IL-12 production via p38 MAPK. Int J Biol Sci, 2010, 7(9): 1298-1310

[13] FanH, HallP, SantosLL, et al.. Macrophage migration inhibitory factor and CD74 regulate macrophage chemotactic responses via MAPK and Rho GTPase. J Immunol, 2011, 186(8): 4915-4924

[14] JohnsonGL, LapadatR. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science, 2002, 298(5600): 1911-1912

[15] RouxPP, BlenisJ. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev, 2004, 68(2): 320-344

[16] LaiCF, ChaudharyL, FaustoA, et al.. Erk is essential for growth, differentiation, integrin expression, and cell function in human osteoblastic cells. J Biol Chem, 2001, 276(17): 14 443-14 450

[17] Deschênes-SimardX, KottakisF, MelocheS, et al.. ERKs in cancer: friends or foes. Cancer Res, 2014, 74(2): 412-419

[18] ZekeA, MishevaM, ReményiA, et al.. JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships. Microbiol Mol Biol Rev, 2016, 80(3): 793-835

[19] WilmerWA, DixonCL, HebertC. Chronic exposure of human mesangial cells to high glucose environments activates the p38 MAPK pathway. Kidney Int, 2001, 60(3): 858-871

[20] SumaraG, FormentiniI, CollinsS, et al.. Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis. Cell, 2009, 136(2): 235-248

[21] LenarcikA, Bidzińska-SpeichertB, Tworowska-BardzińskaU, et al.. Hormonal abnormalities in firstdegree relatives of women with polycystic ovary syndrome (PCOS). Endokrynol Pol, 2011, 62(2): 129-133

[22] RosenfieldRL, MonicaM, KristenW, et al.. Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test. Hum Reprod, 2011, 26(11): 3138-3146

[23] LeeMT, AndersonE, LeeGY. Changes in ovarian morphology and serum hormones in the rat after treatment with dehydroepiandrosterone. Anat Rec, 1991, 231(2): 185-192

[24] WangYX, XieXM, ZhuWJ. Serum adiponectin and resistin levels in patients with polycystic ovarian syndrome and their clinical implications. J Huazhong Univ Sci Technol Med Sci, 2010, 30(5): 638-642

[25] BachJP, DeusterO, BalzerGeldsetzerM, et al.. The role of macrophage inhibitory factor in tumorigenesis and central nervous system tumors. Cancer, 2009, 115(10): 2031-2040

[26] KleemannR, BucalaR, KleemannR, et al.. Macrophage migration inhibitory factor: critical role in obesity, insulin resistance, and associated comorbidities. Mediators Inflamm, 2010, 84(1): 111-116

[27] PedroGM, María PilarM, José AlfredoM, et al.. Differential Proinflammatory and Oxidative Stress Response and Vulnerability to Metabolic Syndrome in Habitual High-Fat Young Male Consumers Putatively Predisposed by Their Genetic Background. Int J Mol Sci, 2013, 14(9): 17 238-17 255

[28] LegroRSV, DanielC, KauffmanRP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Survey, 2004, 59(2): 141-154

[29] OllilaMM, PiltonenT, PuukkaK, et al.. Weight Gain and Dyslipidemia in Early Adulthood Associate with Polycystic Ovary Syndrome: Prospective Cohort Study. J Clin Endocrinol Metab, 2016, 101(2): 739-747

[30] FrankG, RoteNS, JudiM, et al.. Elevated circulating levels of macrophage migration inhibitory factor in polycystic ovary syndrome. Cytokine, 2010, 51(3): 240-244

[31] JorlyM Á, EduardoRV, et al.. Macrophage migration inhibitory factor in obese and non-obese women with polycystic ovary syndrome. Endocrinol Nutr, 2014, 62(1): 31-37

[32] VosslerMR, YaoH, YorkRD, et al.. cAMP activates MAP kinase and Elk-1 through a B-Raf-and Rap1-dependent pathway. Cell, 1997, 89(1): 73-82

[33] Nelson-DegraveVL, WickenheisserJK, HendricksKL, et al.. Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome. Mol Endocrinol, 2005, 19(2): 379-390

[34] LanCW, ChenMJ, TaiKY, et al.. Functional microarray analysis of differentially expressed genes in granulosa cells from women with polycystic ovary syndrome related to MAPK/ERK signaling. Sci Rep, 2015, 5: 14 994

[35] TakahashiK, KogaK, LingeHM, et al.. Macrophage CD74 contributes to MIF-induced pulmonary inflammation. Resp Res, 2009, 10(1): 1-14

[36] LueH, KapurniotuA, Fingerle-RowsonG, et al.. Rapid and transient activation of the ERK MAPK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on JAB1/CSN5 and Src kinase activity. Cell Signal, 2006, 18(5): 688-703

[37] ZerneckeA, BernhagenJ, WeberC. Macrophage migration inhibitory factor in cardiovascular disease. Circulation, 2008, 117(12): 1594-1602