Macrophage Migration Inhibitory Factor Promoter Research Articles

The role of macrophage migration inhibitory factor in autoimmune liver disease

The role of the cytokine, macrophage migration inhibitory factor (MIF), and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Two MIF promoter polymorphisms, a functional -794 CATT5-8 microsatellite repeat (rs5844572) and a -173 G/C single-nucleotide polymorphism (rs755622), were analyzed in DNA samples from over 500 patients with AIH, PBC, and controls. We found a higher frequency of the proinflammatory and high-expression -794 CATT7 allele in AIH, compared to PBC, whereas lower frequency was found in PBC, compared to both AIH and healthy controls. MIF and soluble MIF receptor (CD74) were measured by enzyme-linked immunosorbent assay in 165 serum samples of AIH, PBC, and controls. Circulating serum and hepatic MIF expression was elevated in patients with AIH and PBC versus healthy controls. We also identified a truncated circulating form of the MIF receptor, CD74, that is released from hepatic stellate cells and that binds MIF, neutralizing its signal transduction activity. Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls.These data suggest a distinct genetic and immunopathogenic basis for AIH and PBC at the MIF locus. Circulating MIF and MIF receptor profiles distinguish PBC from the more inflammatory phenotype of AIH and may play a role in pathogenesis and as biomarkers of these diseases.

The macrophage migration inhibitory factor − 173 G/C polymorphism is not significantly associated with necrotizing enterocolitis in preterm infants

Background and PurposeNecrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among premature infants. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that has been implicated in the pathophysiology of inflammatory bowel diseases. The MIF promoter contains a functionally relevant single nucleotide polymorphism (SNP) G→C at position −173, with the MIF −173*C allele being associated with higher MIF expression in vitro and with higher MIF levels in vivo. The aim of this study was to investigate whether the G/C polymorphism at −173 of the MIF promoter is associated with the development of NEC. MethodsIn this retrospective cohort study, 107 preterm infants (GA≤32weeks), of whom 41 had NEC (NEC Stage I n=20, Stage II n=3, Stage III n=18) and 66 were not affected, were genotyped for the MIF −173 SNP. MIF genotyping was carried out by PCR and DHPLC. ResultsWe did not find significant differences in the prevalence of the −173G/C polymorphism and in the distribution of the −173 MIF genotype in infants with NEC compared to controls. Moreover, we did not observe an association between the polymorphism and mortality. ConclusionsThe polymorphism −173G/C of the MIF promoter does not appear to be of major importance in the pathophysiology of NEC in preterm infants.

Macrophage migration inhibitory factor promoter 173G/C polymorphism is associated with atopic dermatitis risk

International Journal of DermatologyVolume 53, Issue 1 p. e75-e77 Correspondence Macrophage migration inhibitory factor promoter 173G/C polymorphism is associated with atopic dermatitis risk Lei Ma MD, PhD, Lei Ma MD, PhD Department of Dermatology, Binzhou Medical University Hospital, Binzhou, China Lei Ma and Hai-Bo Xue contributed equally to this work.Search for more papers by this authorHai-Bo Xue MD, PhD, Hai-Bo Xue MD, PhD Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, China Lei Ma and Hai-Bo Xue contributed equally to this work.Search for more papers by this authorXiu-Hao Guan MD, PhD, Xiu-Hao Guan MD, PhD State Key Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, ChinaSearch for more papers by this authorRui-Qun Qi MD, PhD, Rui-Qun Qi MD, PhD State Key Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, ChinaSearch for more papers by this authorYu-Bo Liu MD, Yu-Bo Liu MD State Key Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, ChinaSearch for more papers by this author Lei Ma MD, PhD, Lei Ma MD, PhD Department of Dermatology, Binzhou Medical University Hospital, Binzhou, China Lei Ma and Hai-Bo Xue contributed equally to this work.Search for more papers by this authorHai-Bo Xue MD, PhD, Hai-Bo Xue MD, PhD Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, China Lei Ma and Hai-Bo Xue contributed equally to this work.Search for more papers by this authorXiu-Hao Guan MD, PhD, Xiu-Hao Guan MD, PhD State Key Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, ChinaSearch for more papers by this authorRui-Qun Qi MD, PhD, Rui-Qun Qi MD, PhD State Key Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, ChinaSearch for more papers by this authorYu-Bo Liu MD, Yu-Bo Liu MD State Key Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang, ChinaSearch for more papers by this author First published: 04 April 2013 https://doi.org/10.1111/j.1365-4632.2012.05597.xCitations: 2 Lei Ma, md, phdDepartment of Dermatology Binzhou Medical University Hospital 661 Second Huanghe Street, Binzhou, 256603, China E-mail: [email protected] Hai-Bo Xue, md, phdDepartment of Endocrinology and Metabolism Binzhou Medical University Hospital 661 Second Huanghe Street Binzhou, 256603 China E-mail:[email protected] Conflicts of interest: None declared. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume53, Issue1January 2014Pages e75-e77 RelatedInformation

Association between MIF gene polymorphisms and carotid artery atherosclerosis

Atherosclerosis is a chronic inflammatory disorder. Macrophage migration inhibitory factor (MIF) is a potent cytokine that plays an important role in the regulation of immune responses. Polymorphisms including five- to eight-repeat CATT variants ((CATT)5–8) and G-173C in the promoter region of the MIF gene are associated with altered levels of MIF gene transcription. The purpose of the study is to investigate the relationship between promoter polymorphisms of the MIF gene and the severity of carotid artery atherosclerosis (CAA). The severity of CAA was assessed in 593 individuals with a history of ischemic stroke by using sonographic examination, and the MIF promoter polymorphisms of these individuals were genotyped. The carriage of (CATT)7 (compared to genotypes composed of (CATT)5, (CATT)6, or both), carriage of C allele (compared to GG), and carriage of the haplotype (CATT)7-C (compared to genotypes composed of (CATT)5-G, (CATT)6-G, or both) were significantly associated with an increase in the severity of CAA. We conclude that polymorphisms in the MIF gene promoter are associated with CAA severity in ischemic stroke patients. These genetic variants may serve as markers for individual susceptibility to CAA.

A genetic role for macrophage migration inhibitory factor (MIF) in adult-onset Still's disease

IntroductionAdult-onset still's disease (AOSD) is a rare systemic inflammatory disorder in which abnormalities in inflammatory cytokines production appear to play a pathophysiological role. Our previous work has reported increased expression of macrophage migration inhibitory factor (MIF) and revealed its correlation with disease severity and activity in AOSD. A -173 G/C single nucleotide polymorphism (SNP) (rs755622) and a -794 CATT5-8 repeat (rs5844572) in the MIF promoter have been reported. In this study, we sought to explore the relationship between functional MIF promoter polymorphisms and MIF expression in AOSD.Methods100 patients and 200 controls were recruited in the study. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was utilized to analyze the -173 G/C SNP (rs755622) and PCR-based size discrimination assay was applied to detect the -794 CATT5-8 repeat (rs5844572) in the MIF promoter. Plasma MIF levels were measured by ELISA. MIF mRNA levels were quantified by real-time reverse transcription (RT)-PCR. Bisulfate genomic sequencing was employed to evaluate DNA methylation status within the MIF promoter.ResultsWe identified that the frequencies of MIF -794 CATT5 (P = 0.001) allele and the expression of MIF (P <0.001) were increased in patients compared to healthy controls. Plasma levels of MIF in patients with CC genotype were higher than those of patients with GC or GG genotypes (P = 0.05). In patients with established AOSD, a higher frequency of -794 CATT7 containing MIF genotypes was observed in those with liver dysfunction (P = 0.009). Haplotype analysis revealed a higher representation of the MIF haplotype defined by -173*C/-794 CATT5 (C5) in AOSD patients (P = 0.001).ConclusionFunctional promoter polymorphisms in the MIF gene influence plasma MIF levels in AOSD and may contribute to disease susceptibility or clinical presentation of AOSD.

Macrophage migration inhibitory factor gene polymorphisms in inflammatory bowel disease: An association study in New Zealand Caucasians and meta-analysis

To investigate the association of macrophage migration inhibitory factor (MIF) promoter polymorphisms with inflammatory bowel disease (IBD) risk. One thousand and six New Zealand Caucasian cases and 540 Caucasian controls were genotyped for the MIF SNP -173G > C (rs755622) and the repeat polymorphism CATT₅₋₈ (rs5844572) using a pre-designed TaqMan SNP assay and capillary electrophoresis, respectively. Data were analysed for single site and haplotype association with IBD risk and phenotype. Meta-analysis was employed, to assess cumulative evidence of association of MIF -173G > C with IBD. All published genotype data for MIF -173G > C in IBD were identified using PubMed and subsequently searching the references of all PubMed-identified studies. Imputed genotypes for MIF -173G > C were generated from the Wellcome Trust Case Control Consortium (and National Institute of Diabetes and Digestive and Kidney Diseases). Separate meta-analyses were performed on Caucasian Crohn's disease (CD) (3863 patients, 6031 controls), Caucasian ulcerative colitis (UC) (1260 patients, 1987 controls), and East Asian UC (416 patients and 789 controls) datasets using the Mantel-Haenszel method. The New Zealand dataset had 93% power, and the meta-analyses had 100% power to detect an effect size of OR = 1.40 at α = 0.05, respectively. In our New Zealand dataset, single-site analysis found no evidence of association of MIF polymorphisms with overall risk of CD, UC, and IBD or disease phenotype (all P values > 0.05). Haplotype analysis found the CATT₅/-173C haplotype occurred at a higher frequency in New Zealand controls compared to IBD patients (0.6 vs 0.01; P = 0.03, OR = 0.22; 95%CI: 0.05-0.99), but this association did not survive bonferroni correction. Meta-analysis of our New Zealand MIF -173G > C data with data from seven additional Caucasian datasets using a random effects model found no association of MIF polymorphisms with CD, UC, or overall IBD. Similarly, meta-analysis of all published MIF -173G > C data from East Asian datasets (416 UC patients, 789 controls) found no association of this promoter polymorphism with UC. We found no evidence of association of MIF promoter polymorphisms with IBD.

Gastric cancer susceptibility in gastric cancer relatives: Attributable risks of Macrophage migration inhibitory factor promoter polymorphism and Helicobacter pylori

The purpose of this study is to assess attributable effects of Macrophage migration inhibitory factor (MIF) promoter region polymorphisms and Helicobacter pylori infection to the susceptibility to gastric cancer. 296 individuals from non-cardia gastric cancer case families and 319 individuals from control families were obtained from Henan Province, China. The results showed the frequencies of MIF (-173 C/C and -794 non-CATT5carrier) genotypes were significantly higher in the family members of gastric cancer cases than that in the controls family (-173: OR=2.59; -794: OR=2.65), and the ORs reduced with decreasing relative degrees. Multivariate analysis showed that MIF-173 C and -794 non-CATT5 alleles synergized with H. pylori for the risk of gastric cancer (OR=14.64). The attributable risk percent (ARP) and the population attributable risk percent (PARP) attributed to interaction of MIF-173 C/C and MIF-794 non-CATT5carrier were 72.3% and 4.7%, respectively. The MIF risk genotypes and H. pylori conferred a joint ARP of 93.2% to gastric cancer. In summary, Possession of -173 G→C substitution and -794 non-CATT5carrier in the MIF promoter region are associated with increased susceptibility to non-cardia gastric cancer. H. pylori infection increases the risks of MIF polymorphisms for susceptibility with gastric cancer.

Macrophage Migration Inhibitory Factor Is Involved in a Positive Feedback Loop Increasing Aromatase Expression in Endometriosis

Immune-endocrine interplay may play a major role in the pathogenesis of endometriosis. In the present study, we have investigated the interaction between macrophage migration inhibitory factor (MIF), a major pro-inflammatory and growth-promoting factor markedly expressed in active endometriotic lesions, and estradiol (E(2)) in ectopic endometrial cells. Our data showed a significant increase of MIF protein secretion and mRNA expression in endometriotic cells in response to E(2). MIF production was blocked by Fulvestrant, an estrogen receptor (ER) antagonist, and induced by ERα and ERβ selective agonists propyl-pyrazole-triol (PPT) and diarylpropionrile (DPN), respectively, thus demonstrating a specific receptor-mediated effect. Cell transfection with MIF promoter construct showed that E(2) significantly stimulates MIF promoter activity. Interestingly, our data further revealed that MIF reciprocally stimulates aromatase protein and mRNA expression via a posttranscriptional mRNA stabilization mechanism, that E(2) itself can upregulate aromatase expression, and that inhibition of endogenous MIF, using MIF specific siRNA, significantly inhibits E(2)-induced aromatase. Thus, the present study revealed the existence of a local positive feedback loop by which estrogen acts directly on ectopic endometrial cells to upregulate the expression of MIF, which, in turn, displays the capability of inducing the expression of aromatase, the key and rate-limiting enzyme for estrogen synthesis. Such interplay may have a considerable impact on the development of endometriosis.

Influence of MIF, CD40, and CD226 polymorphisms on risk of rheumatoid arthritis

Macrophage migration inhibitory factor (MIF) is a key pro-inflammatory mediator. It plays an important role part in the pathogenesis of several inflammatory and immune diseases. A functional single nucleotide polymorphism (SNP) of MIF -173 G/C is known to influence MIF promoter activity in T lymphoblast cell lines and is associated with a higher serum MIF level. The CD40 is also crucial for some relevant functions of the immune system and may be related to rheumatoid arthritis (RA). And CD226 is an important cell-surface receptor molecule involved in the adhesion and activation of T-cell. We hypothesized that these polymorphisms may contribute to RA susceptibility. We studied MIF -173 G/C, CD40, and CD226 gene polymorphisms in 214 patients with RA and 478 controls in a Chinese population. Genotyping was done by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). When the MIF -173 GG homozygote genotype was used as the reference group, the CC genotype was associated with a significantly increased risk for RA. In the recessive model, when the MIF -173 GG/GC genotypes were used as the reference group, the CC homozygote genotype was associated with a significant 1.56-fold increased susceptibility to RA. None of the CD40 rs1883832 C/T and CD226 rs763361 C/T polymorphisms achieved a significant difference in genotype distributions between cases and controls. In the stratification analyzes, a significantly increased risk for RA associated with the MIF -173 CC genotype was evident among CRP-negative patients compared with the MIF -173 GG/GC genotype. For the CD40 rs1883832 C/T variant, the risk effects of CD40 rs1883832 TT versus CD40 rs1883832 CC/CT were significant in men. These findings suggested that the functional SNP MIF -173 G/C variant allele was associated with the development of RA. However, CD40 and CD226 gene polymorphisms may not be associated with RA susceptibility. Due to the limitation of sample size, this study should be considered preliminary.

Macrophage Migration Inhibitory Factor -173 G/C Polymorphism is Not Associated with An Increased Risk of Necrotizing Enterocolitis in Preterm Neonates in NICU

Background: Necrotizing Enterocolitis (NEC) is a leading cause of morbidity and mortality among preterm neonates. To identify subsets of neonates at high risk of NEC is a challenge. Local pro-inflammatory response of the host could be of relevance in the still unclear pathogenesis of NEC. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, implicated in the pathophysiology of inflammatory bowel diseases, such as chronic colitis and gastric inflammation. The MIF promoter contains a functionally relevant single nucleotide polymorphism (SNP) G/C at position -173. The MIF -173 C allele is associated with higher MIF expression in vitro.

Association between macrophage migration inhibitory factor promoter region polymorphism (-173 G/C) and cancer: a meta-analysis

BackgroundMacrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine upstream of many inflammatory cytokines. MIF is implicated in several acute and chronic inflammatory conditions. MIF's promoter region has functional single nucleotide polymorphisms that controls MIF expression and protein levels. Since increased plasma MIF levels are associated with cancer, studies have examined the association between Mif promoter polymorphisms and cancer. This study is a meta-analysis of the available studies on such an association.ResultsA total of 5 studies were included in this meta-analysis to include 1116 cases (cancer patients) and 1728 controls (no cancer). Carrying any C allele in the Mif -173 G/C promoter polymorphism resulted in a significantly greater risk for developing cancer [OR = 1.89 (1.15-3.11), p = 0.012)] when compared to the (G/G) genotype. Subgroup analysis revealed that this association was significant only for "solid" tumors (including gastric and prostate cancers) [OR = 2.67 (1.26-5.65), p = 0.010] but not for "non-solid" tumors (leukemia) [OR = 1.21 (0.95-1.55), p = 0.122]. Furthermore, when only prostate tumor studies were included in the analysis, the association became even stronger [OR = 3.72 (2.55-5.41), p < 0.0001].ConclusionsMeta-analysis suggests there is an association between any C allele in the Mif -173 G/C promoter polymorphism and an increased risk of cancer, particularly for solid tumors. The association appeared stronger for prostate cancer, specifically. Future studies that include different types of cancers are needed to support and extend these observations.

Single Nucleotide Polymorphisms Alter the Promoter Activity of Bovine MIF

Macrophage migration inhibitory factor (MIF) is a unique pro-inflammatory cytokine whose chief functions include modulating TLR4 expression, and suppressing the anti-inflammatory effects of glucocorticoids. Not surprisingly, MIF is involved in a number of inflammatory diseases and single nucleotide polymorphisms (SNPs) have been implicated in modulating disease severity. The objective of the present study was to determine if SNPs in 5′ region of bovine MIF affects its promoter activity. Three SNPs were identified, -1078A>G, -395A>G, and -400G>C, all of which fall within predicted transcription factor binding regions. Reporter gene assays indicate that the identified SNPs have a significant effect of modulating MIF promoter activity. Finally, gene association analysis suggests a significant relationship of -395A>G with the susceptibility to Mycobacterium avium ssp. paratuberculosis infection, the causative agent of Johne's disease. Given the relationships revealed in the current study, it is clear that the role of MIF in bovine diseases such as Johne's disease merits further investigation.

Tandem Repeats of the Catt Element of Macrophage Migration Inhibitory Factor Gene May Predict Gestational Diabetes Mellitus Severity

Previous investigations have demonstrated the association of the CATT repeated allele in the Macrophage migration inhibitory factor (MIF) with obesity and diabetes. Since there are common risk factors and molecular pathways in Type 2 Diabetes and Gestational Diabetes Mellitus (GDM), we focused on the associations of MIF variation with GDM. In a case-control study we enrolled 157 GDM and 217 healthy pregnant women, referred to the outpatient clinic of Shariati Hospital. The different repeats of CATT in MIF promoter were determined. MIF relative gene expression was evaluated in Peripheral blood mononuclear cells of all the participants. The GDM group had higher mean age and pre-gravid BMI. Also fasting serum glucose, insulin and MIF gene expression were significantly higher in the GDM patients. The statistically significant difference was observed between GDM and a healthy group in carrying 7-CATT allele and MIF gene expression. Regarding GDM risk factors, MIF 7-CATT allele showed significant relation with pre-pregnancy obesity, as well as the need for insulin therapy. Our results indicate that an association between MIF genotypes and its expression with GDM, obesity and the need of insulin for management of GDM patients exists.

A Polymorphism in the Macrophage Migration Inhibitory Factor Promoter Is Associated With Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) is a common adverse outcome of prematurity, causing severe morbidity and mortality. The cytokine macrophage migration inhibitory factor (MIF) has been recently shown to favor murine fetal lung development. In this prospective study, we evaluate the expression of MIF in the lung and in the serum of preterm infants (n = 50) and investigate whether the -173 G/C MIF promoter polymorphism is associated with the risk of BPD (n = 103). MIF was highly expressed in lung tissue from preterm infants. Serum MIF levels were measured by ELISA at d 1 after birth. MIF levels were increased [median (interquartile range), 71.01 (44.9-162.3) ng/mL], particularly in those infants with RDS [110.4 (59.4-239.2) ng/mL] compared with healthy adults [2.4 (1.2-5.0) ng/mL], (p < 0.001). The MIF -173*C allele, which predisposes to higher MIF production, was associated with a lower incidence of BPD (OR, 0.2; 95% CI, 0.04-0.93), independently from mechanical ventilation and oxygen exposure (p = 0.03). In conclusion, these data show that MIF expression is increased in lung and serum of preterm infants and suggest that the high producing MIF -173*C allele may be a protective factor for BPD.

Identification of a novel cell type-specific intronic enhancer of macrophage migration inhibitory factor (MIF) and its regulation by mithramycin

The aim of this study was to determine the genetic regulation of macrophage migration inhibitory factor (MIF). DNase I hypersensitivity was used to identify potential hypersensitive sites (HS) across the MIF gene locus. Reporter gene assays were performed in different human cell lines with constructs containing the native or mutated HS element. Following phylogenetic and transcription factor binding profiling, electrophoretic mobility shift assay (EMSA) and RNA interference were performed and the effects of incubation with mithramycin, an antibiotic that binds GC boxes, were also studied. An HS centred on the first intron of MIF was identified. The HS acted as an enhancer in human T lymphoblasts (CEMC7A), human embryonic kidney cells (HEK293T) and human monocytic cells (THP-1), but not in a fibroblast-like synoviocyte (FLS) cell line (SW982) or cultured FLS derived from rheumatoid arthritis (RA) patients. Two cis-elements within the first intron were found to be responsible for the enhancer activity. Mutation of the consensus Sp1 GC box on each cis-element abrogated enhancer activity and EMSA indicated Sp1 binding to one of the cis-elements contained in the intron. SiRNA knock-down of Sp1 alone or Sp1 and Sp3 together was incomplete and did not alter the enhancer activity. Mithramycin inhibited expression of MIF in CEMC7A cells. This effect was specific to the intronic enhancer and was not seen on the MIF promoter. These results identify a novel, cell type-specific enhancer of MIF. The enhancer appears to be driven by Sp1 or related Sp family members and is highly sensitive to inhibition via mithramycin.

Functional promoter polymorphisms of macrophage migration inhibitory factor in peptic ulcer diseases

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator, which plays a pivotal role in inflammatory and immune diseases. We attempted to clarify the association of functional polymorphisms of MIF gene promoter with the development of gastro-duodenal ulcer. The study was performed in 471 stocked DNAs obtained from the subjects, including 93 healthy volunteers, with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. In all 471 DNAs, 92 and 43 were obtained from gastric and duodenal ulcer patients, respectively. By an unadjusted analysis, infection with Helicobacter pylori (H. pylori), male gender and non-steroidal anti-inflammatory drug (NSAID/aspirin) use were significantly associated with a risk for developing a gastric ulcer, whereas MIF promoter polymorphisms were not. On the other hand, infection with H. pylori, male gender and 7-CATT repeat at position -794 were significantly associated with the development of a duodenal ulcer, whereas NSAID/ aspirin use was not. By the analysis after adjustment for age, gender, NSAID/aspirin use and H. pylori infection status, 7/7-CATT homozygote had a significantly increased risk for the development of duodenal ulcers (OR, 6.31; 95% CI, 1.50-26.6; p=0.012). No factors were significantly associated with the development of peptic ulcers in NSAID/aspirin users. Our results suggested that tetranucleotide repeat polymorphism of MIF gene promoter might be associated with the development of duodenal ulcers.

Polymorphisms in the macrophage migration inhibitory factor gene and bone loss in postmenopausal women

Osteoporosis is a severe condition in postmenopausal women and a common cause of fracture. Osteoporosis is a complex disease with a strong genetic impact, but susceptibility is determined by many genes with modest effects and environmental factors. Only a handful of genes consistently associated with osteoporosis have been identified so far. Inflammation affects bone metabolism by interfering with the interplay between bone resorption and formation, and many inflammatory mediators are involved in natural bone remodeling. The cytokine macrophage migration inhibitory factor (MIF) has been shown to affect bone density in rodents, and polymorphisms in the human MIF promoter are associated with inflammatory disorders such as rheumatoid arthritis. We investigated the association of polymorphisms in the MIF gene with bone mineral density (BMD) and bone loss in 1002 elderly women using MIF promoter polymorphisms MIF-CATT 5 – 8 and rs755622(G/C) located −794 and −173 bp upstream of the transcriptional start site. Bone loss was estimated both by the change in BMD over 5 years and by the levels of bone resorption markers in serum measured at four occasions during a 5-year period. The MIF-CATT 7/rs755622(C) haplotype was associated with increased rate of bone loss during 5 years at the femoral neck ( p < 0.05) and total hip ( p < 0.05). In addition, the MIF-CATT 7/rs755622(C) haplotype carriers had higher levels of the bone turnover marker serum C-terminal cross-linking telopeptide of type I collagen (S-CTX-I, p < 0.01) during the 5 year follow-up period. There was no association between MIF-CATT 7/rs755622(C) and baseline BMD at femoral neck, total hip or lumbar spine. We conclude that MIF promoter polymorphisms have modest effects on bone remodeling and are associated with the rate of bone loss in elderly women.

Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer

Macrophage migration inhibitory factor (MIF) is a well-described proinflammatory mediator. MIF overexpression has been observed in many tumors and is implicated in oncogenic transformation and tumor progression. However, the molecular mechanisms responsible for regulating MIF expression remain poorly understood. In this study, we showed that the transcriptional repressor HBP1 (HMG box-containing protein 1) negatively regulates MIF expression. We first identified a large high-affinity HBP1 DNA-binding element at positions -811 to -792 from the transcriptional start site within the MIF promoter by computer analysis. Reporter analyses showed that this element was required for HBP1-mediated transcriptional repression. Furthermore, HBP1 associated with the MIF promoter in vivo and repressed endogenous MIF gene expression. Consistent with HBP1-mediated repression of MIF, low levels of HBP1 expression were associated with high levels of MIF expression in prostate cancer samples. Importantly, HBP1-mediated repression of MIF inhibited tumorigenic growth and invasion, and the repressive effect of HBP1 on tumorigenic growth and invasion could be partially rescued by the addition of recombinant MIF to the culture medium. Finally, prostate tumor samples with low HBP1 and high MIF expression were associated with a significant decrease in relapse-free survival. Taken together, these results indicated that HBP1 directly inhibited MIF gene transcription, and suggested that the loss of HBP1 expression or activity may contribute to the upregulation of MIF expression in prostate tumor tissue.

Molecular characterization and functional analysis of porcine macrophage migration inhibitory factor (MIF) gene

Originally identified as a cytokine that inhibits the migration of macrophages from capillaries, MIF has now emerged to be a multifunctional factor involved in immune response, glucose and lipid metabolism. We report here the molecular characterization of porcine MIF gene, which resides on chromosome 14q21.3 and encodes 114 amino acids. Porcine MIF mRNA was found to be highly expressed in stomach, to a lesser extent in spleen, and at the lowest levels in skeletal muscle and heart. To gain further insight into the functional regulation of MIF, we cloned the porcine MIF promoter and verified its functionality using luciferase reporter assay. In NIH 3T3 cells, the endogenous MIF mRNA level was up-regulated by rosiglitazone treatment in a dose-dependent manner, which was accompanied by a concurrent increase in peroxisome proliferator-activated receptor (PPAR)gamma2 transcription. Over-expression of porcine PPARgamma2 in NIH 3T3 cells could also up-regulate the transcription of MIF in the absence of rosiglitazone treatment. These observations are consistent with the bioinformatic analysis that reveals two potential PPAR binding sites within the MIF promoter. Additionally, the over-expression of resistin, a factor considered to be a link between inflammation and metabolic signals, could remarkably down-regulate the transcription of MIF in NIH 3T3 cells. Taken together, we proposed that the transcription of MIF is induced by activation of PPARgamma2 and inhibited by excessive resistin.

Histone deacetylase inhibitors repress macrophage migration inhibitory factor (MIF) expression by targeting MIF gene transcription through a local chromatin deacetylation

The cytokine macrophage migration inhibitory factor plays a central role in inflammation, cell proliferation and tumorigenesis. Moreover, macrophage migration inhibitory factor levels correlate with tumor aggressiveness and metastatic potential. Histone deacetylase inhibitors are potent antitumor agents recently introduced in the clinic. Therefore, we hypothesized that macrophage migration inhibitory factor would represent a target of histone deacetylase inhibitors. Confirming our hypothesis, we report that histone deacetylase inhibitors of various chemical classes strongly inhibited macrophage migration inhibitory factor expression in a broad range of cell lines, in primary cells and in vivo. Nuclear run on, transient transfection with macrophage migration inhibitory factor promoter reporter constructs and transduction with macrophage migration inhibitory factor expressing adenovirus demonstrated that trichostatin A (a prototypical histone deacetylase inhibitor) inhibited endogenous, but not episomal, MIF gene transcription. Interestingly, trichostatin A induced a local and specific deacetylation of macrophage migration inhibitory factor promoter-associated H3 and H4 histones which did not affect chromatin accessibility but was associated with an impaired recruitment of RNA polymerase II and Sp1 and CREB transcription factors required for basal MIF gene transcription. Altogether, this study describes a new molecular mechanism by which histone deacetylase inhibitors inhibit MIF gene expression, and suggests that macrophage migration inhibitory factor inhibition by histone deacetylase inhibitors may contribute to the antitumorigenic effects of histone deacetylase inhibitors.