Serum Macrophage Migration Inhibitory Factor Concentrations Research Articles

Association of Serum Macrophage Migration Inhibitory Factor with 3-Month Poor Outcome and Malignant Cerebral Edema in Patients with Large Hemispheric Infarction.

We aimed to investigate the associations of macrophage migration inhibitory factor (MIF), toll-like receptors 2 and 4 (TLR2/4), and matrix metalloproteinase 9 (MMP9) with 3-month poor outcome, death, and malignant cerebral edema (MCE) in patients with large hemispheric infarction (LHI). Patients with LHI within 24h of onset were enrolled consecutively. Serum MIF, TLR2/4, and MMP9 concentrations on admission were measured. Poor outcome was defined as a modified Rankin Scale score of ≥ 3 at 3months. MCE was defined as a decreased level of consciousness, anisocoria and midline shift > 5mm or basal cistern effacement, or indications for decompressive craniectomy during hospitalization. The cutoff values for MIF/MMP9 were obtained from the receiver operating characteristic curve. Of the 130 patients with LHI enrolled, 90 patients (69.2%) had 3-month poor outcome, and MCE occurred in 55 patients (42.3%). Patients with serum MIF concentrations ≤ 7.82ng/mL for predicting 3-month poor outcome [adjusted odds ratio (OR) 2.827, 95% confidence interval (CI) 1.144-6.990, p = 0.024] also distinguished death (adjusted OR 4.329, 95% CI 1.841-10.178, p = 0.001). Similarly, MMP9 concentrations ≤ 46.56ng/mL for predicting 3-month poor outcome (adjusted OR 2.814, 95% CI 1.236-6.406, p = 0.014) also distinguished 3-month death (adjusted OR 3.845, 95% CI 1.534-9.637, p = 0.004). Lower serum MIF and MMP9 concentrations at an early stage were independently associated with 3-month poor outcomes and death in patients with LHI. These findings need further confirmation in larger sample studies.

A Bidirectional Mendelian Randomization Analysis of Circulating Inflammatory Cytokines with Colon and Rectum Cancers

Chronic inflammation has been proposed to be associated with tumor development and progression. Dynamic changes in serum cytokines induced by feedback mechanisms from tumors make differentiation of cause and effect difficult. In this study, a bidirectional summary-level Mendelian randomization (MR) analysis was performed to elucidate the causal correlation between inflammatory regulators with colon (CC) and rectum (RC) carcinomas. Summary-level data on inflammation-related genetic variations were extracted from a genome-wide association meta-analysis. Corresponding data for CC and RC were obtained from the FinnGen (CC: 1396 cases vs. 174,006 controls; RC: 1,078 cases vs. 174,006 controls) and UK Biobank (CC: 2,226 cases vs. 358,968 controls; RC: 1,170 cases vs. 360,024 controls) consortiums. Inverse-variance weighted MR was used as the primary method, and sensitivity analysis was performed to assess the MR assumptions. After P value correction and meta-analysis, there was evidence of direct associations between macrophage migration inhibitory factor (MIF) and CC (95% confidence interval (CI):1.001-1.003; P = 8.77×10-4) and inverse correlations between Interleukin-17 (IL-17) and RC (95% CI: 0.997-0.999; P = 1.15×10-3). Conversely, interleukin-1 receptor antagonist (IL1ra) was downregulated in patients at a higher risk of RC (P = 0.006), and no reliable results revealed a causal association between other cytokines and CC and RC. Thus, this MR study suggests that downregulated serum MIF and elevated serum IL-17 concentrations may reduce the risk of CC and RC, respectively. Therefore, MIF and IL-17 may serve as potential therapeutic targets, and further exploration of their underlying mechanisms is warranted.

Salivary and serum concentrations of monocyte chemoattractant protein-1, macrophage inhibitory factor, and fractalkine in relation to rheumatoid arthritis and periodontitis.

Monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibitory factor (MIF), and fractalkine are chemokines that are expressed by a variety of cell types to regulate macrophage inflammatory response. The aim of the study was to examine the effects of periodontitis and rheumatoid arthritis (RA) on their serum and salivary concentrations. Adults with either periodontitis (P, n=21), or with rheumatoid arthritis (RA, n=23), or with both diseases (RA+P, n=23) were included in the study. Systemically and periodontally healthy individuals (n=22) served as controls. Saliva and serum samples were collected from all participants before the medical and periodontal examinations. Salivary and serum MCP-1, MIF, and fractalkine concentrations were measured by the Luminex technique. Total salivary protein levels were determined by the Bradford assay. Salivary MCP-1, MIF, and fractalkine concentrations were elevated in both RA groups (RA+P and RA) in comparison with systemically healthy controls. As related to total salivary protein levels, higher MCP-1 (P=0.003) and fractalkine (P=0.045) concentrations were found in controls compared with the P group. In serum, MCP-1 concentrations in the RA+P group were higher (P=0.003) than those of group P. Elevated serum fractalkine concentrations were observed in both periodontitis groups (RA+P, P=0.014; and P, P=0.013) compared with controls. In RA, MCP-1, MIF, and fractalkine concentrations are elevated in saliva. These chemokines may disrupt oral macrophage responses and potentially take part in the interaction between periodontitis and RA.

Measurement of serum macrophage migration inhibitory factor (MIF) and correlation with severity and pruritus scores in client owned dogs with atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disease of dogs. Macrophage migration inhibitory factor (MIF) initiates pro-inflammatory cytokine release in human AD and serum concentrations are correlated with disease severity. Canine serum MIF concentrations are increased in dogs with AD and correlate with clinical lesion and pruritus scores. Client owned dogs (n=49) diagnosed with AD and 17 healthy, unaffected control dogs were used for the study. A commercially available MIF ELISA was optimized for the dog and serum from clinical cases used. Information regarding treatment, Canine Atopic Dermatitis Extent and Severity Index, (CADESI-4) and pruritus Visual Analog Scale (pVAS) were recorded for each dog at the time of serum collection. Dogs with AD which had not received steroid therapy and those treated with oclacitinib had significantly elevated serum MIF concentrations compared to controls. Concentrations of MIF were not significantly different in AD dogs receiving steroids compared to controls. There was no significant correlation between MIF concentrations and clinical scores (CADESI-4 or pVAS). Serum MIF concentrations are increased in dogs with AD and MIF might be a target for therapy.

Serum macrophage migration inhibitory factor is correlated with atrial fibrillation.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine secreted by macrophages. This study is performed to investigate whether serum MIF is correlated with atrial fibrillation (AF). Totally, 186 AF patients and 103 healthy controls were enrolled in this study. AF patients were then divided into paroxysmal AF, persistent AF, and permanent AF subgroups. There were higher serum MIF concentrations in AF patients than in healthy subjects. Logistic regression analysis demonstrated that serum MIF was associated with AF. Permanent AF patients exhibited higher serum MIF concentrations than persistent and paroxysmal AF subgroups. Elevated serum MIF concentrations were found in persistent AF patients compared with paroxysmal AF patients. Moreover, serum MIF concentrations were associated with left atrial diameter after Spearman correlation analysis.

Association between the MIF-173G/C Polymorphism and Serum MIF levels with Pulmonary Tuberculosis: A Meta-analysis

Many studies have indicated that Macrophage migration inhibitory factor (MIF)-173G/C gene polymorphisms are associated with susceptibility to pulmonary tuberculosis (PTB). Additionally, some studies have suggested that there are higher levels of serum MIF in patients with PTB than the controls. However, the results of these studies were underpowered. The current study aimed to precisely evaluate the association between the MIF-173G/C polymorphism and serum MIF concentrations with PTB. Therefore, a systematic literature search was preformed to identify studies involving the indicated association. Eleven articles (1316 cases and 1272 controls) were included in the study. The results indicated that the MIF-173G/C polymorphism was significantly associated with PTB susceptibility, especially in Asians. Interestingly, the results further detected that circulating MIF levels were significantly higher in patients with PTB than in healthy controls, but this was only the case among Asians. Moreover, the statistical significance was also similar to that of the high quality group. The present study indicated that the MIF-173G/C polymorphism may contribute to the development of PTB. Furthermore, significantly higher serum MIF levels were observed in PTB patients than in controls, which further indicated that the MIF may play an important role in PTB progression, particularly in Asians.

Macrophage migration inhibitory factor as a novel cerebrospinal fluid marker for neurosyphilis among HIV-negative patients

BackgroundNeurosyphilis (NS) is difficult to diagnose, especially in syphilis patients with negative cerebrospinal fluid (CSF) rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) tests. MethodsWe conducted a cross-sectional study and an analysis of macrophage migration inhibitory factor (MIF) in syphilitic patients to identify a novel marker for the diagnosis of NS, with a focus on probable NS (NS with negative VDRL/RPR tests). For this purpose, CSF and serum MIF concentrations were determined in 43 NS and 43 syphilis/non-NS (N-NS) patients at the Zhongshan Hospital of the Medical College of Xiamen University from July 2014 to June 2015. Sixty-three blood donors were used as healthy controls. ResultsNS patients had higher CSF (median [IQR]: 8.77ng/ml [4.76–19.13]) and serum (52.58ng/ml [28.31–95.94]) MIF concentrations than N-NS patients did (4.08 [2.21–9.68] and 34.30 [19.77–59.75], respectively). Using a cut-off point of 6.63ng/ml, CSF MIF had a sensitivity of 74.42% and a specificity of 67.74% for the diagnosis of NS. The sensitivity was higher than that of CSF RPR (39.53%) and increased protein (48.84%) tests and similar to that of CSF pleocytosis (67.44%). Additionally, the sensitivity of CSF MIF, which was 92.31% for the diagnosis of probable NS, was higher than that of CSF pleocytosis (65.38%) and increased protein (53.85%) tests. By integrating all CSF parameters (pleocytosis, increased protein and MIF), the sensitivity would be improved to 100% by parallel testing, which would avoid missed diagnoses. Moreover, the specificity would be improved to 100% by the serial testing algorithm, which would again avoid misdiagnosis. ConclusionsCSF MIF concentrations can be used as a novel CSF marker to establish or exclude a diagnosis of NS.

Iron Deficiency Anaemia is Associated with Decreased Levels of Macrophage Migration Inhibitory Factor and Monocyte Chemoattractant Protein-1

Many bodily systems are affected by iron deficiency anaemia (IDA), including the immune system. However, the pathophysiological mechanisms whereby this anaemia promotes deterioration in immunity remain largely unexplained. In order to enlighten this pathophysiological link , serum levels of macrophage migration inhibitory factor (MIF) and monocyte chemoattractant protein-1 (MCP-1), which play an important roles in a healthy functioning immune system, were examined in patients with IDA and healthy volunteers. A total of 30 patients with IDA (mean age 33.6±7.8 years, 30% male) and 30 healthy individuals (mean age 30.1 ± 8.8 years, 27 % male) were included. Serum MIF and MCP-1 levels were measured in a sandwich-assay format, using commercial enzyme-linked immunosorbent assay kits. There was no statistically significant difference in age and gender distribution between participants with IDA and controls (p>0.05). Serum MIF and MCP-1 concentrations were lower in the IDA group than in the control group (p < 0.005, and p < 0.01, respectively). When considering the role of MIF and MCP-1 in maintaining the normal immune response of the organism, a decrease in production in patients with IDA may contribute to immune dysfunction in these individuals.

Serum and salivary macrophage migration inhibitory factor in patients with oral squamous cell carcinoma.

The overexpression of macrophage migration inhibitory factor (MIF) has been identified in a variety of tumors and the investigation of its molecular mechanisms in tumor progression is a key topic of research. The present study aimed to investigate MIF as a potential marker for disease control or recurrence, and to assess the association between serum and salivary MIF and the clinicopathological characteristics of patients with oral squamous cell carcinoma (OSCC). Serum and salivary samples were collected prior to and following the surgical treatment of 50 patients with OSCC. MIF concentrations were assessed by enzyme-linked immunosorbent assay and the adopted level of statistical significance was P<0.05. The results revealed that serum MIF concentrations were significantly reduced following tumor resection in OSCC patients. Furthermore, higher preoperative salivary MIF concentrations were observed in patients with larger tumors and in those who succumbed to the disease. In conclusion, high salivary and serological MIF concentrations were identified in patients with OSCC. Nevertheless, only serological MIF concentrations may be considered as a potential marker for the early detection of OSCC recurrence once the salivary levels, prior and following treatment, do not show any significant differences.

Significance of the vascular endothelial growth factor and the macrophage migration inhibitory factor in the progression of hepatocellular carcinoma

The aim of the present study was to investigate the expression of vascular endothelial growth factor (VEGF) and macrophage migration inhibitory factor (MIF) in HCC progression and their correlation with clinicopathological factors as well as the relationship between their expression levels. The expression of serum VEGF and MIF was evaluated in 150 patients with HCC and in 30 normal volunteers by enzyme-linked immunosorbent assay (ELISA). VEGF and MIF expression levels were evaluated by immunohistochemistry on tissue microarrays containing 150 HCCs with paired adjacent non-cancer liver tissues. VEGF and MIF mRNA levels were determined by quantitative PCR in another 48 HCCs. The correlation of VEGF and MIF with clinicopathological factors was analyzed in HCC. Serum VEGF and MIF concentrations were higher in HCC patients than the levels in the controls. The expression levels of VEGF and MIF in the HCC tissues were both higher than those in the adjacent non-tumor liver tissues. Overexpression of VEGF and MIF was significantly associated with tumor size (P=0.027 and 0.022, respectively), intrahepatic metastasis (P=0.032 and 0.027, respectively), vascular invasion (P=0.044 and 0.039, respectively) and TNM stage (P=0.028 and 0.013, respectively). Furthermore, VEGF and MIF mRNA levels were higher in HCC compared to levels in the paired non-cancer liver tissues. VEGF and MIF mRNA levels were correlated with tumor stage and metastasis. The expression of VEGF was positively related with MIF expression in HCC. The expression of MIF and VEGF in HCC was markedly positively correlated, which suggests that MIF and VEGF play an important role in the progression of HCC. Both factors may concomitantly accelerate the progression of HCC.

Serum levels of macrophage migration-inhibitory factor (MIF) have diagnostic, predictive and prognostic roles in epithelial ovarian cancer patients

Macrophage migration-inhibitory factor (MIF) plays an important role in the pathogenesis of multiple malignancies, and its expression strongly also affects outcomes of cancer patients. The objective of this study was to determine the clinical significance of serum levels of MIF in epithelial ovarian cancer (EOC) patients. A total of 50 patients with a pathologically confirmed diagnosis of EOC were enrolled into this study. Serum MIF concentrations were determined using the solid-phase sandwich ELISA method. Age- and sex-matched 30 healthy controls were included in the analysis. Median age of patients was 56.5 years old, range 22 to 83 years. Majority of the patients had an advanced disease (International Federation of Gynecologists and Obstetricians (FIGO) stages III and IV) (90%). Baseline serum MIF levels were significantly higher than those in the healthy control group (p = 0.005). No known clinical variables including histology, grade of histology, stage of disease, debulking surgery, and serum CA 125 levels were found to be correlated with serum MIF levels (p > 0.05). Only those chemotherapy-unresponsive patients had higher serum MIF levels compared with responsive ones (p = 0.02). Patients with elevated serum MIF concentrations had significantly unfavorable overall survival compared to those with lower levels (p = 0.01). However, a serum MIF level was found to play no prognostic role for progression-free survival (p = 0.09). In conclusion, serum levels of MIF have diagnostic, predictive, and prognostic roles in EOC patients.

Relationship of macrophage migration inhibitory factor levels in PBMCs, lesional skin and serum with disease severity and activity in vitiligo vulgaris

Melanocyte loss in vitiligo vulgaris is believed to be an autoimmune process. Macrophage migration inhibitory factor (MIF) is involved in many autoimmune skin diseases. We determined the possible role of MIF in the pathogenesis of vitiligo vulgaris, and describe the relationship between MIF expressions and disease severity and activity. Serum MIF concentrations and mRNA levels in PBMCs were measured in 44 vitiligo vulgaris patients and 32 normal controls, using ELISA and real-time RT-PCR. Skin biopsies from 15 patients and 6 controls were analyzed by real-time RT-PCR. Values are reported as median (25th-75th percentile). Serum MIF concentrations were significantly increased in patients [35.81 (10.98-43.66) ng/mL] compared to controls [7.69 (6.01-9.03) ng/mL]. MIF mRNA levels were significantly higher in PBMCs from patients [7.17 (3.59-8.87)] than controls [1.67 (1.23-2.42)]. There was also a significant difference in MIF mRNA levels in PBMCs between progressive and stable patients [7.86 (5.85-9.13) vs 4.33 (2.23-8.39)] and in serum MIF concentrations [40.47 (27.71-46.79) vs 26.80 (10.55-36.07) ng/mL]. In addition, the vitiligo area severity index scores of patients correlated positively with changes of both serum MIF concentrations (r = 0.488) and MIF mRNA levels in PBMCs (r = 0.426). MIF mRNA levels were significantly higher in lesional than in normal skin [2.43 (2.13-7.59) vs 1.18 (0.94-1.83)] and in patients in the progressive stage than in the stable stage [7.52 (2.43-8.84) vs 2.13 (1.98-2.64)]. These correlations suggest that MIF participates in the pathogenesis of vitiligo vulgaris and may be useful as an index of disease severity and activity.

Macrophage migration-inhibitory factor is elevated in pregnant women with gestational diabetes mellitus

Objective: In reports, abnormal macrophage migration-inhibitory factor (MIF) production has been associated with several diseases. Furthermore, despite scarce data, increasing evidence suggest that MIF plays a central role in glucose homeostasis and in the development of type 1 and type 2 diabetes. However, serum MIF levels in gestational diabetes mellitus (GDM) have not yet been investigated. To address this question, we performed a prospective study between a group of pregnant women with GDM and healthy pregnant controls. Materials and methods: GDM group consisted of 43 pregnant women, whereas the control group consisted of 40 healthy pregnant women. In the morning after an overnight fast, venous blood was sampled for the measurement of serum concentrations of insulin and MIF. Serum was separated by centrifugation and immediately stored at −80°C until the assay. Results: There was no significant difference between the groups for maternal characteristics. Women with GDM had significantly higher levels of serum insulin (14.37 ± 9.92 µU/ml vs. 8.78 ± 4.35 µU/ml; p = 0.001) and serum MIF concentrations (11.31 ± 4.92 ng/ml vs. 5.31 ± 4.07 ng/ml; p < 0.001) when compared with healthy pregnant control group. Conclusion: Our data demonstrated that serum levels of MIF are significantly elevated in patients with GDM. Our findings indicate that MIF might have a role in GDM; however, there is a need for further investigation.

Different profiles of cytokine expression during mild and severe acute pancreatitis.

To study secretion patterns of pro- and anti-inflammatory cytokines, and activation of various cellular subsets of leukocytes in peripheral blood. We have conducted a prospective observational study. One hundred and eight patients with a diagnosis of acute pancreatitis and onset of the disease within last 72 h were included in this study. The mRNA expression of 25 different types of cytokines in white blood cells was determined by quantitative real time polymerase chain reaction. Levels of 8 different cytokines in blood serum were measured by enzyme linked immunosorbent assay. Clinical data and cytokine expression results were subjected to statistical analysis. Severe and necrotizing acute pancreatitis (AP) is characterized by the significant depletion of circulating lymphocytes. Severe acute pancreatitis is associated with a typical systemic inflammatory response syndrome and over-expression of pro-inflammatory cytokines [interleukin (IL)-6, IL-8, macrophage migration inhibitory factor (MIF)]. Serum IL-6 and MIF concentrations are the best discriminators of severe and necrotizing AP as well as possible fatal outcome during the early course of the disease. Deregulation of cellular immune system is a key event leading to severe and necrotizing AP. IL-6 and MIF could be used as early predictors of complications.

Elevated Serum Macrophage Migration Inhibitory Factor (MIF) Concentrations in Chronic Kidney Disease (CKD) Are Associated with Markers of Oxidative Stress and Endothelial Activation

Chronic kidney disease (CKD) carries an increased risk of cardiovascular disease (CVD). Macrophage migration inhibiting factor (MIF) is a proinflammatory cytokine implicated in the pathogenesis of sepsis, autoimmune disease, atherogenesis, and plaque instability, and is a known cardiac depressant. This post-hoc, cross-sectional study examined whether MIF serum concentrations are elevated in CKD patients. Our study included CKD 3-5 patients with moderate to severe renal dysfunction (n = 257) (mean age SD; 55 +/- 12 years) and 53 controls (60 +/- 12 years). Serum MIF concentrations, measured by enzyme-linked immunosorbent assay (ELISA), were studied in relation to glomerular filtration rate (GFR), presence of CVD, outcome and inflammatory and oxidative stress markers. MIF was significantly elevated in CKD patients compared with controls (CKD: median 676 [range 118-8275 pg/mL] controls: 433 [142-4707] pg/mL; P = 0.008). MIF was also associated with 8-hydroxy-2-deoxyguanosine (8-OH-dG) levels (rho = 0.26; P = 0.001), a marker of oxidative stress, and ICAM-1 levels (rho = 0.14; P = 0.02), a marker of endothelial activation. However, the elevated MIF concentrations were neither correlated with glomerular filtration rate (GFR) nor inflammatory markers such as CRP, IL-6, and TNF. When combining MIF and IL-6 as a marker of inflammation, a significant increase in risk for CVD was found, but when analyzing all-cause mortality, this did not differ significantly with regard to mortality from inflamed patients with low MIF levels. The data suggest that increased serum MIF levels found in CKD is not caused primarily by poor renal function, but is associated with markers of oxidative stress and endothelial activation and may play a role in vascular disease associated with CKD.

The Diagnostic Value of Macrophage Migration Inhibitory Factor (MIF) in Gastric Cancer

The present study was conducted to investigate the sensitivity, specificity, predictive values and accuracy of serum MIF, CEA, CA 19-9 levels and their various combinations in patients with gastric cancer. Study group consists of pathologically verified, gastric cancer (n = 63) and apparently healthy controls (n = 50). Serum MIF concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Serum values of patients were significantly higher than the controls (p = 0.011). Diagnostic sensitivity and specificity, predictive values and accuracies were calculated for each marker and their various combinations. The best results were achieved with the marker combination of MIF-CEA-CA 19-9 and MIF-CEA combination. In our opinion, the combination of the markers MIF-CEA is a valuable diagnostic tool for gastric cancer.

Macrophage Migration Inhibitory Factor in Cancer

The objective of this study was to investigate the expression of macrophage migration inhibitory factor (MIF) in patients with colorectal cancer (GIS) and malignant melanoma (MM). The study group consists of pathologically verified colorectal cancer (n = 63) and malignant melanoma (n = 65) pateints and healthy controls (n = 25). Serum MIF concentrations were determined by enyzme-linked immunosorbent assay. Serum values of the patients were significantly higher than the controls (p < 0.001 for GIS, p = 0.032 for MM). Diagnostic sensitivity and specificity were calculated for MIF for colorectal and malignant melanoma. The results demonstrate that colorectal cancer express and secrete large amounts of MIF.

Association of Systemic Concentrations of Macrophage Migration Inhibitory Factor With Impaired Glucose Tolerance and Type 2 Diabetes

Macrophage migration inhibitory factor (MIF) is a central cytokine in innate immunity. MIF expression can be regulated by glucose and insulin, but data on the association with type 2 diabetes are sparse. The aim of this study was to test whether MIF is associated with impaired glucose tolerance (IGT) and type 2 diabetes and whether these associations are independent of metabolic and immunological risk factors and to compare the associations of MIF and IGT/type 2 diabetes with those of C-reactive protein (CRP) and interleukin-6 (IL-6) with IGT/type 2 diabetes. The Cooperative Health Research in the Region of Augsburg/Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4 (KORA S4) is a population-based survey performed in Southern Germany (1999-2001). Of 1,653 participants aged 55-74 years, 236 patients with type 2 diabetes, 242 subjects with IGT, and 244 normoglycemic control subjects matched for age and sex were included in this cross-sectional study. Serum concentrations of MIF were measured by enzyme-linked immunosorbent assay. Serum MIF concentrations are highly increased in individuals with IGT and type 2 diabetes. The associations of MIF with IGT and type 2 diabetes were independent of classical risk factors and of CRP and IL-6 and were much stronger before and after multivariate adjustment than the associations of CRP and IL-6 with IGT and type 2 diabetes. Our data suggest that elevations of systemic MIF concentrations precede the onset of type 2 diabetes. This finding may be relevant because MIF has been reported to contribute to the development of type 2 diabetes-related diseases such as atherosclerosis and cancer.

Increased Levels of Macrophage Migration Inhibitory Factor in Sera of Patients with Escherichia coli O157:H7-Induced Enterocolitis

Verotoxin-producing Escherichia coli O157:H7 is a pathogen that causes severe hemorrhagic enterocolitis and sometimes leads to serious conditions such as hemolytic-uremic syndrome. Various inflammatory parameters have been assessed for their efficacy in predicting the severity of E. coli O157:H7-induced colitis (9, 10), but no serological biomarker has been identified which can precisely determine the presence and severity of this colitis. Macrophage migration inhibitory factor (MIF) is a unique cytokine that has been shown to play a role in several inflammatory diseases (4, 7). We here report increased levels of MIF in sera of patients with verotoxin-producing E. coli O157:H7-induced enterocolitis. Serum samples were obtained from 24 patients with E. coli O157:H7-induced enterocolitis, 30 sex- and age-matched patients with bacterial enterocolitis induced by pathogens other than O157:H7 (Salmonella, Vibrio, and non-verotoxigenic E. coli) as disease controls, and 55 healthy individuals as normal controls. Serum MIF concentrations were measured with an enzyme-linked immunosorbent assay specific for MIF (IDLISA; Sapporo Immunodiagnostic Laboratory, Sapporo, Japan) as described previously (7). E. coli O157:H7 was diagnosed by stool culture, which is the gold standard diagnostic method for this pathogen. As shown in Fig. ​Fig.1,1, the serum MIF levels in patients with E. coli O157:H7-induced enterocolitis (23.67 ± 2.36 ng/ml; P < 0.001 versus normal controls and disease controls) were sixfold higher than those in normal controls and threefold higher than those in disease controls (3.99 ± 0.17 and 8.23 ± 0.60 ng/ml, respectively). Furthermore, serum MIF levels provided a level of differentiation of subjects with E. coli O157:H7-induced enterocolitis that was comparable to that afforded by detection of E. coli O157:H7 from stool culture (cutoff value, sensitivity, specificity, and positive predictive value by serum MIF: 12.5 ng/ml, 0.875, 0.950, and 0.840, respectively). On the other hand, leukocyte counts and levels of C-reactive protein in peripheral blood samples were increased in patients with E. coli O157:H7-induced enterocolitis and disease controls compared with normal controls, but there was no significant difference between patients with E. coli O157:H7-induced enterocolitis and disease controls (data not shown). FIG. 1. Serum MIF concentrations in infectious colitis induced by verotoxin-producing E. coli O157:H7. Values are means ± standard error. Serum MIF levels were measured in 55 normal controls (NC), 30 patients with bacterial colitis induced by pathogens ... We previously demonstrated that MIF is a pivotal cytokine in the pathogenesis of inflammatory bowel disease and other types of colitis (8). In addition, recent studies have shown that MIF is immediately released in large quantities from the pituitary and other tissues in response to lipopolysaccharide (LPS) (1, 3). In particular, increased MIF levels in serum have been reported in patients with endotoxemias such as sepsis (4, 6). In mice, targeted disruption of MIF diminishes the immune response to LPS (2). Thus, MIF is considered to be an important molecule in the development of endotoxemia and subsequent severe inflammation. It has been hypothesized that LPS is involved in the pathophysiology of verotoxigenic E. coli infection (5). In this study, we showed that serum MIF levels were markedly increased in patients with verotoxin-producing E. coli O157:H7-induced colitis compared with those in patients with nonspecific colitis and healthy individuals. These findings suggest that the acute-phase response of circulating MIF to the endotoxin induced by E. coli O157:H7 plays a role in the development of enterocolitis. Although further studies are needed to clarify the role of MIF in the pathophysiology of E. coli O157:H7-induced colitis, MIF may make a major contribution to the development of enterocolitis caused by verotoxigenic E. coli O157:H7.

Obesity, macrophage migration inhibitory factor, and weight loss

Elevated macrophage migration inhibitory factor (MIF) has been implicated as a causal mechanism in a number of disease conditions including cardiovascular disease (CVD), diabetes, and cancer. Excess body fat is associated with an increased risk of numerous health conditions including CVD, diabetes, and cancer. To our knowledge, the association between MIF and obesity status and the effect of weight loss on serum MIF concentrations have not been reported. In this study, we examined the effects of participation in a behavior-based weight loss program on MIF concentrations in obese individuals. Study participants were 71 men and women enrolled in The Cooper Institute Weight Management Program. Participants were predominantly female (68%, n=48), middle-aged (46.5+/-9.8 y), and severely obese (BMI=43.0+/-8.6). Plasma MIF concentrations and other standard risk factors were measured before and after participation in a diet and physical activity based weight management program. The mean follow-up was 8.5+/-3.0 months with an average weight loss of 14.4 kg (P<0.001). The majority of clinical risk factors significantly improved at follow-up. Median levels of plasma MIF concentration were significantly lower at follow-up (median [IQR]; 5.1[3.6-10.3]) compared to baseline (8.4 [4.3-48.8]; P=0.0005). The percentage of participants with plasma MIF concentration > or =19.5 mg/nl (highest tertile at baseline) decreased from 33.8 to 5.6% (P<0.001). Further, elevated baseline plasma MIF concentration was associated with markers of beta-cell dysfunction and reductions in MIF were associated with improvements in beta-cell function. Circulating MIF concentrations are elevated in obese but otherwise healthy individuals; however, this elevation in MIF is not uniform across individuals. In obese individuals with elevated circulating MIF concentrations, participation in physical activity and a dietary-focused weight management program resulted in substantial reduction in MIF.