A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1 We identified MIF as a PARP-1–dependent AIF-associated nuclease that is required for parthanatos. In response to oxidative stress or DNA damage, PARP-1 activation triggers AIF release from the mitochondria. AIF then recruits MIF to the nucleus where MIF cleaves genomic DNA into large fragments and causes cell death. Depletion of MIF, disruption of AIF and MIF interaction, or blocking MIF nuclease activity inhibited chromatinolysis and parthanatos. Targeting MIF nuclease activity may offer an important therapeutic opportunity for a variety of disorders with excessive PARP-1 activation.( Science 2016)
Migration inhibitory factor for guinea pig macrophages was the first lymphokine to be discovered (Bloom and Bennett,1966;David, 1966). Expression of MIF activity was found to correlate well with delayed hypersensitivity and cellular immunity in humans. MIF activity could be detected in the synovia of patients with rheumatoid arthritis. The
expression of MIF at sites of inflammation suggested a role for the mediator in regulating the function of macrophages in host defense. The symbol MIF is also used for Mullerian inhibitory factor, but to avoid confusion, AMH, for anti-Mullerian hormone, has been declared the preferred symbol for the latter gene.
NCBI Summary:
This gene encodes a lymphokine involved in cell-mediated immunity, immunoregulation, and inflammation. It plays a role in the regulation of macrophage function in host defense through the suppression of anti-inflammatory effects of glucocorticoids. This lymphokine and the JAB1 protein form a complex in the cytosol near the peripheral plasma membrane, which may indicate an additional role in integrin signaling pathways. [provided by RefSeq, Jul 2008]
General function
Ligand, Growth factor
Comment
Cellular localization
Secreted
Comment
candidate123. //////////A possible link between luteinizing hormone and macrophage migration inhibitory factor levels in polycystic ovary syndrome. Calan M et al. (2016) Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that plays a role in metabolic and inflammatory processes. Increasing evidence suggests that there is a link between MIF and ovulation. We aimed to evaluate plasma MIF levels in women with polycystic ovary syndrome (PCOS) and to determine whether MIF levels differ between the follicular phase and mid-cycle of the menstrual cycle in eumenorrheic women. Ninety women with PCOS and 80 age- and BMI-matched healthy eumenorrheic women were consecutively recruited into this prospective observational study. For all subjects, plasma MIF levels in the early follicular phase were measured by ELISA; for the 40 healthy controls, MIF levels were also measured during mid-cycle of the same menstrual cycle. Plasma MIF levels were significantly higher in women with PCOS than in eumenorrheic women (14.16 ± 1.59 vs. 10.39 ± 0.70 ng/ml; p < 0.001). MIF levels were significantly higher at mid-cycle than in the follicular phase in eumenorrheic women (11.15 ± 0.61 vs. 10.56 ± 0.82 ng/ml; p < 0.001). MIF was positively correlated with BMI, high sensitivity C-reactive protein (hs-CRP), and homeostasis model assessment of insulin resistance (HOMA-IR) in both groups. MIF was positively correlated with luteinizing hormone (LH) and free-testosterone only in the PCOS group. Binary logistic regression analyses revealed that the odds ratio (OR) for PCOS independently increases linearly with elevated MIF (OR = 1.385, 95% CI = 1.087-1.764, p = 0.017). MIF may play a crucial role in the reproductive system in women, including the development of PCOS and normal ovulation.//////////////////
Ovarian function
Ovulation
Comment
Wada et al. (1999) demonstrated that HCG can induce the elevation of serum and follicular fluid MIF concentrations through the stimulation of ovarian cells, and that MIF is probably involved in the mechanism of ovulation.
Elevated circulating levels of macrophage migration inhibitory factor in polycystic ovary syndrome. Gonzlez F et al. Women with polycystic ovary syndrome (PCOS) have chronic low level inflammation which can increase the risk of atherogenesis. We evaluated the status of circulating macrophage migration inhibitory factor (MIF), a proinflammatory cytokine involved in atherogenesis, in women with PCOS and weight-matched controls. Two-way analysis of variance models adjusted for age were fit to evaluate the effect of PCOS status (PCOS vs. controls) and weight-class (obese vs. lean) on MIF and other parameters. MIF levels were significantly (p<0.001) higher in women with PCOS (lean: 37.7+/-10.6ng/ml; obese: 54.6+/-15.2ng/ml) compared to controls (lean: 4.8+/-0.6ng/ml; obese: 17.5+/-8.0ng/ml) regardless of weight-class. CRP levels were significantly (p<0.001) higher in obese subjects (PCOS: 6.2+/-1.9mg/l; controls: 6.7+/-1.4mg/l) compared to lean subjects (PCOS: 0.9+/-0.4mg/l; controls: 0.2+/-01mg/l) after controlling for PCOS status. MIF levels directly correlated with % truncal fat (r=0.41, p<0.05), and plasma levels of CRP (r=0.42, p=0.05), LH (r=0.45, p=0.04), testosterone (r=0.53, p<0.008), androstendione (r=0.58, p<0.005). IS(OGTT) inversely correlated with plasma levels of MIF (r=-0.51, p<0.02) and CRP (r=-0.73, p<0.001). Circulating MIF is elevated in PCOS independent of obesity, but both PCOS and obesity contribute to a proatherogenic state. In PCOS, abdominal adiposity and hyperandrogenism may exacerbate the risk of atherosclerosis.
Expression regulated by
LH
Comment
MIF concentrations in the culture media of human granulosa cells increased with HCG stimulation Wada et al. (1999)
Ovarian localization
Oocyte, Granulosa, Luteal cells, Large luteal cells
Comment
The presence of MIF protein in human granulosa cells was confirmed by Western blot analysis (Wada et al., 1997).Neilson L, et al 200 reported molecular phenotyping of the human oocyte by PCR-SAGE.
Consecutive application of PCR and serial analysis of gene expression (SAGE) was used to generate a
catalog of approximately 50,000 SAGEtags from nine human oocytes. Matches for known genes were
identified using the National Institutes of Health SAGEtag database. Matches in the oocyte SAGE catalog
were found for surface receptors, second-messenger systems, and cytoskeletal, apoptotic, and secreted
proteins, including the gene decribed here.
Follicle stages
Preovulatory, Corpus luteum
Comment
Bove SE et al 2000 reported that immunohistochemical analysis revealed that MIF was present in the
bovine CL throughout the estrous cycle and appeared to be localized to large
luteal cells. It was concluded that MIF is produced within the bovine CL, mRNA
expression is maximal in the early CL, and the protein is primarily localized
to large luteal cells.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 mutations
Species: mouse
Mutation name: None
type: None fertility: subfertile Comment:Matsuura T, et al 2002 reported that anti-macrophage inhibitory factor antibody inhibits
PMSG-hCG-induced follicular growth and ovulation in mice.
Mice were primed with an intraperitoneal injection of pregnant mare
serum gonadotropin (PMSG) and were treated with an anti-rat MIF antibody and
human chorionic gonadotropin (hCG) to induce ovulation. After that, the
ovulated ova were counted. the ovaries were studied using standard
histological procedures.
Ovaries treated with the anti-MIF antibody showed reduced numbers of
growing follicles surrounded by granulosa cells and theca cells with a little
proliferation compared with the control. The average numbers of ova collected
from mice treated with the anti-MIF antibody were reduced compared with those
collected from control mice.
Anti-MIF antibody inhibits the follicular growth and ovulation in
mice, and MIF may play an important role in the inflammatory reactions during
follicle growth and ovulation.
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: First evidence of genetic association between the MIF-173G/C single-nucleotide polymorphisms and polycystic ovary syndrome. Li C et al. (2011) The purpose of this study was to investigate whether polymorphism of MIF gene is associated with PCOS. The MIF-173G/C single-nucleotide polymorphism (SNP) was detected in 529 PCOS patients and 585 healthy female controls of Chinese Han ancestry. The association of the gene variants with clinical and metabolic parameters and hormone levels was investigated. The frequencies of genotypes and allelotypes of the MIF-173G/C SNP did significantly differ between women with PCOS and healthy controls (P = 0.017 and P = 0.003, respectively). They did significantly differ between obese PCOS patients and obese controls (P = 0.029 and P = 0.039, respectively). The MIF-173 CC and CG genotypes were associated with higher body mass index (BMI) and waist-to-hip ratio (WHR) in both PCOS patients (P < 0.001, P = 0.001) and normal controls (P < 0.001, P = 0.002). The PCOS patients with CC and CG genotypes had higher fasting plasma glucose levels (P < 0.001), higher fasting insulin levels (P < 0.001), and higher HOMA-IR (P < 0.001) compared with patients with the GG genotype. The MIF-173G/C polymorphism is associated with PCOS in Chinese Han women and may contribute to the phenotypic expression of PCOS.//////////////////