Macrophage Inhibitory Factor Levels Research Articles

Systemic immune profile in Prader-Willi syndrome: elevated matrix metalloproteinase and myeloperoxidase and reduced macrophage inhibitory factor

BackgroundPrader-Willi syndrome (PWS) is a rare genetic neurodevelopmental syndrome with highly increased risk of obesity and cardiovascular disease (CVD). Recent evidence suggests that inflammation is implicated in the pathogenesis. Here we investigated CVD related immune markers to shed light on pathogenetic mechanisms.MethodsWe performed a cross-sectional study with 22 participants with PWS and 22 healthy controls (HC), and compared levels of 21 inflammatory markers that reflect activity in different aspects of CVD related immune pathways and analyzed their association with clinical CVD risk factors.ResultsSerum levels of matrix metalloproteinase 9 (MMP-9) was (median (range)) 121 (182) ng/ml in PWS versus 44 (51) ng/ml in HC, p = 1 × 10-9), myeloperoxidase (MPO) was 183 (696) ng/ml versus 65 (180) ng/ml, p = 1 × 10-5) and macrophage inhibitory factor (MIF) was 46 (150) ng/ml versus 121 (163) ng/ml (p = 1 × 10-3), after adjusting for age and sex. Also other markers tended to be elevated (OPG, sIL2RA, CHI3L1, VEGF) but not significantly after Bonferroni correction (p > 0.002). As expected PWS had higher body mass index, waist circumference, leptin, C-reactive protein, glycosylated hemoglobin (HbA1c), VAI and cholesterol, but MMP-9, MPO and MIF remained significantly different in PWS after adjustment for these clinical CVD risk factors.ConclusionPWS had elevated levels of MMP-9 and MPO and of reduced levels of MIF, which were not secondary to comorbid CVD risk factors. This immune profile suggests enhanced monocyte/neutrophil activation, impaired macrophage inhibition with enhanced extracellular matrix remodeling. These findings warrant further studies targeting these immune pathways in PWS.

Macrophage inhibiting factor in women with habitual miscarriage in pregnancy following immunocytotherapy

The aim of our study was to evaluate the macrophage inhibitory factor (MIF) content of in peripheral blood serum, as well as MIF production by mitogen-stimulated cells from whole peripheral blood during pregnancy in women with idiopathic recurrent miscarriage who received immunocytotherapy both prior to and in the first trimester of pregnancy. The study involved 51 women 20 to 40 years old: 10 fertile healthy females beyond pregnancy, 23 women with idiopathic recurrent miscarriage (IRM), 18 women with a physiological course of pregnancy at different stages of gestation (12, in the first trimester; 12, in the second; 9, in third trimester). MIF content was assessed by multiplex analysis using flow fluorometry. Of 23 women with IRM, six lost their pregnancy in the first trimester, 14 women prolonged pregnancy to the full-term resulting into birth of a healthy child; three had premature births at 24 to 35 weeks with a live fetus. There were no intergroup differences in the serum MIF level in control women and in patients with IRM, both beyond and during pregnancy. However, the dynamics of this index during pregnancy, was similar with increase during the II and III trimesters in both groups of women (control and with IRM). During pregnancy, the dynamics of MIF production by mitogen-activated cells from peripheral blood was also similar, except for values in the II trimester: in this period, MIF production in women with IRM was significantly lower, although it was still increased 3 times compared to the 1st trimester (5-fold to controls). In women with physiological pregnancy, the serum MIF levels at 5 to 6 weeks were lower than in women in both IRM subgroups, but there was no difference in MIF content for women with miscarriage and full-term pregnancy. Similarly, there were no differences of MIF contents in the supernates of activated whole blood cells of women at the time of study within groups and between the groups at the same time of examination. It has been shown that ICT has a positive effect on the course and outcomes of pregnancy in women with pregnancy prolonged to full-term. The serum MIF content in women with full-term pregnancy is higher than in women with miscarriage, which is consistent with results of other authors about adverse developmental effects of low serum MIF levels at early pregnancy terms. The results obtained indicate that immunocytotherapy do not regularly promote pregnancy to full term in women with IPV. Therefore, further research is required to find out criteria for administering ICT in treatment of idiopathic recurrent miscarriage.

Macrophage inhibitory factor (MIF) gene polymorphisms are associated with disease susceptibility and with circulating MIF levels in active non-segmental vitiligo in patients from western Mexico.

BackgroundThe macrophage migration inhibiting factor (MIF) is a protein that promotes the activation of immune cells and the production of other proinflammatory cytokines such as TNF‐α, IL‐1β, and IFN‐γ, which have proposed to play an essential role in the pathogenesis of vitiligo. The study aimed to assess the association between MIF polymorphisms (−794 CATT5‐8 and −173 G>C), MIF in situ expression, and MIF serum concentrations with susceptibility and disease activity in patients with non‐segmental vitiligo (NSV) from western Mexico.MethodsThe study included 111 patients with NSV and 201 control subjects. Genotyping was performed by conventional PCR (−794 CATT5‐8) and PCR‐RFLP (−173 G>C) methods. MIF mRNA expression was quantified by real‐time PCR and MIF serum concentrations were determined by ELISA kit. Histopathological samples were analyzed by automated immunohistochemistry.ResultsThe MIF polymorphisms were associated with NSV susceptibility. Serum concentrations of MIF were higher in patients with active NSV and correlated negatively with the years of evolution. The depigmented skin from patients with active vitiligo showed a high expression of MIF.Conclusion MIF polymorphisms increase the risk of NSV in the western Mexican population. The serum concentrations of MIF and in situ expression are associated with active NSV.

Serum and cerebrospinal fluid cytokines in children with acute encephalopathy

BackgroundThe pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified. MethodsLevels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis). ResultsThe CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC. ConclusionOur results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis.

L–lysine ameliorates sepsis-induced acute lung injury in a lipopolysaccharide-induced mouse model

Sepsis is a severe, life-threatening condition caused primarily by the cellular response to infection. Sepsis leads to increased tissue damage and mortality in patients in the intensive care unit. L-Lysine is an essential amino acid required for protein biosynthesis and is abundant in lamb, pork, eggs, red meat, fish oil, cheese, beans, peas, and soy. The present study investigates the protective effect of L-lysine against sepsis-induced acute lung injury (ALI) in a lipopolysaccharide-induced mouse model. In the present study, mice were divided into sham, control, 5 mg/kg body weight L-lysine, and 10 mg/kg body weight L-lysine treatment groups. At the end of the treatment period, we determined the levels of oxidative and inflammatory markers, myeloperoxidase (MPO) and catalase activities, total cell count, the wet/dry ratio of lung tissue, and total protein content. The effects of L-lysine on the cellular architecture of lung tissue were also evaluated. L-Lysine treatment significantly reduced the magnitude of lipid peroxidation; total protein content; wet/dry ratio of lung tissue; tumor necrosis factor alpha, interleukin-8, and macrophage inhibitory factor levels; MPO activity; and total cell, neutrophil, and lymphocyte counts. It also increased the levels of reduced glutathione and the activities of glutathione peroxidase, superoxide dismutase, and catalase. A normal cellular architecture was noted in mice in the sham group, whereas proinflammatory changes such as edema and neutrophilic infiltration were detected in mice in the control group. L-lysine significantly ameliorated these proinflammatory changes. Taking all these data together, it is suggested that the L-lysine was effective against sepsis-induced ALI.

L-Lysine protects against sepsis-induced chronic lung injury in male albino rats

Sepsis is a severe, life-threatening condition primarily caused by the cellular response to infection. Sepsis leads to increased tissue damage and mortality in patients in the intensive care unit. L-Lysine is an essential amino acid required for protein biosynthesis and is abundant in lamb, pork, eggs, red meat, fish oil, cheese, beans, peas, and soy. Male albino rats were divided into sham, control, 10-mg/kg bwt L-lysine, and 20-mg/kg bwt L-lysine groups. At the end of treatment, we determined the levels of oxidative and inflammatory markers, myeloperoxidase (MPO) and catalase activities, total cell count, the wet/dry ratio of lung tissue, and total protein content. Furthermore, the effect of L-lysine on the cellular architecture of lung tissue was evaluated. L-Lysine significantly reduced the magnitude of lipid peroxidation; total protein content; wet/dry ratio of lung tissue; tumor necrosis factor-alpha, interleukin-8, and macrophage inhibitory factor levels; MPO activity; and total cell, neutrophil, and lymphocyte counts, and it increased the reduced glutathione levels and the glutathione peroxidase, superoxide dismutase, and catalase activities. A normal cellular architecture was noted in rats in the sham group, whereas proinflammatory changes, such as edema and neutrophilic infiltration, were detected in rats in the control group. L-lysine significantly ameliorated these proinflammatory changes. Thus, L-lysine has the potential for the treatment of sepsis-induced CLI.

Prognostication of Late Cardiac Remodeling in Patients With STEMI Underwent Successful Percutaneous Coronary Intervention: the Role of Macrophage Inhibitory Factor

Background: Macrophage inhibitory factor (MIF) plays a pivotal role in late adverse cardiac remodeling in acute ST-segment elevation myocardial infarction (STEMI). The aim of the study was to investigate the predictive role of the circulating MIF in adverse cardiac remodeling in STEMI patients undergoing percutaneous coronary intervention (PCI). Methods: A total of 73 patients with confirmed acute STEMI successfully treated with PCI were enrolled for participation in the study. Control group was included 20 healthy volunteers. All patients signed informed consent to participate in the study. Echo and Doppler, biomarker assay and MIF determinations were performed at baseline and at 6 month after study entry. Results: There were significant differences (P<0.001) between the levels of MIF in control group (573.75 ng/mL; 95% CI = 397.80 to 1016.75 ng/mL) and entire STEMI patient population (2582.80 ng/mL; 95% CI = 1308.40 to 4122.20 ng/mL). The entire STEMI patient population was divided by the median of the MIF level as follow: the first group consisted of STEMI patients with MIF ≤ 2582.80 ng/ mL (n = 36), and the second group consisted of STEMI patients with the levels of MIF > 2582.80 ng/mL (n = 37). We found that cut-off MIF level ≥2644.5 ng/ml at baseline predicted adverse cardiac remodeling (AUC = 0.736, 95% CІ = 0.515 to 0.956, Р=0.0362; sensitivity = 72.7%; specificity = 81.8%; positive predictive value = 52.7%; negative predictive value = 32.4%; positive likelihood ratio = 0.89 and negative likelihood ratio = 0.72). Conclusions: The MIF level ≥2644.5 ng/mL might be predictor for late adverse cardiac remodeling after STEMI.

Effect of treating glioblastoma with a cytokine inhibitor, ibudilast, in combination with temozolomide on survival in a patient-derived xenograft model.

2062 Background: Recurrence in patients with glioblastoma (GBM) is inevitable, even in patients with O-6-Methylguanine-DNA Methyl Transferase ( MGMT) methylation. We identified increased expression of the inflammatory cytokine, Macrophage Inhibitory Factor (MIF) and its receptor CD74 in patients with recurrent tumors. High levels of MIF and CD74 were associated with poor overall survival in GBM patients. This study aims to determine efficacy of Ibudliast (MN-166; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) to block MIF expression and decrease tumor burden. Ibudilast is an anti-inflammatory drug that was developed for the treatment of bronchial asthma. Methods: The patient derived cell lines (PDCLs) RN1 ( MGMT unmethylated), BAH1 ( MGMT methylated), and HW1 ( MGMT methylated) were treated in vitrowith different concentrations of ibudilast in combination with temozolomide (TMZ). Patient derived xenograft (PDX) models of GBM were developed and treated with the combination of ibudilast and TMZ. Overall survival was calculated. Results: Regardless of MGMT status, significant synergism between ibudilast and TMZ was observed in the PDCLs. Efficacy was associated with significantly decreased expression of its targets, MIF and CD74. Downstream proteins such as Src and Akt were also significantly inhibited. The combination induced apoptosis. RN1 tumors were established intracranially in Balb/c nude mice. Significant increases in survival times of the mice were recorded when treated with the combination. Conclusions: Ibudilast in combination with TMZ resulted in significant blockage of MIF expression, increased apoptosis and longer survival in vivo. A human pilot study for recurrent GBM patients is underway.

P01.20 Treatment of recurrent glioblastoma with the cytokine inhibitor, ibudilast in combination with temozolomide

BACKGROUND: Recurrence in patients with glioblastoma (GBM) is inevitable, even in patients with O-6-Methylguanine-DNA Methyl Transferase (MGMT) methylation. We identified increased expression of the inflammatory cytokine, Macrophage Inhibitory Factor (MIF) and its receptor CD74 in patients with recurrent tumours. High levels of MIF and CD74 were associated with poor overall survival in GBM patients. This study aims to determine efficacy of Ibudliast (AV411; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) to block MIF expression and decrease tumour burden. Ibudilast is an anti-inflammatory drug that was developed for the treatment of bronchial asthma. METHODS: The patient derived cell lines (PDCLs) RN1 (MGMT unmethylated), BAH1 (MGMT methylated), and HW1 (MGMT methylated) were treated in vitro with different concentrations of ibudilast in combination with temozolomide (TMZ). Patient derived xenograft (PDX) models of GBM were developed and treated with the combination of ibudilast and TMZ. Overall survival was calculated. Results: Regardless of MGMT status, significant synergism between ibudilast and TMZ was observed in the PDCLs. Efficacy was associated with significantly decreased expression of its targets, MIF and CD74. Downstream proteins such as Src and Akt were also significantly inhibited. The combination induced apoptosis. RN1 and HW1 tumors were established intracranially in Balb/c nude mice. Significant increases in survival times of the mice were recorded when treated with the combination. CONCLUSION: Ibudilast in combination with TMZ resulted in significant blockage of MIF expression, increased apoptosis and longer survival in vivo. A human pilot study for recurrent GBM patients is underway.

Efficacy and Therapeutic Potential of Curcumin Against Sepsis-Induced Chronic Lung Injury in Male Albino Rats.

The present study investigates curcumin effect against sepsis-induced chronic lung injury (CLI) of male albino rats. Rats were grouped into four groups such rats undergoing a sham cecal ligature puncture (CLP), rats undergoing CLP, rats undergoing CLP and treated with saline and rats undergoing CLP and treated with curcumin (100 mg/kg bwt). After 45 days of treatment, bronchoalveolar fluid (BALF), blood and lung tissues were collected from the each animal. The total protein content, wet and dry (W/D) weight of lung tissues and some inflammatory cells in the BALF were measured. Histopathological analysis was carried out to investigate the alteration of the cellular architecture of lung tissues. Lipid peroxidation malondialdehyde (MDA), superoxide dismutase (SOD) and myeloperoxidase (MPO) levels were determined. Cytokines such as interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-a) and macrophage inhibitory factor (MIF) were measured in the BALF. Curcumin administration significantly reduced CLP-induced inflammation and pulmonary edema. Curcumin treatment is significantly reduced MPO activity, and inflammatory cell accumulation in the BALF and also protein level, MDA, SOD, and W/D ratio were significantly reduced in the lung tissues. Also, curcumin reduced the expression of IL-A, TNF-a and MIF levels in the lung tissues. Histopathological study revealed the significant reduction of CLP-induced CLI in the curcumin-treated male albino rats. Taking all these data together, it is concluded that curcumin can act as a suitable therapeutic agent against CLP-induced CLI of male albino rats.

Exogenous recombinant adiponectin improves survival in experimental abdominal sepsis.

Adiponectin, which has anti-inflammatory features, is an important substance in several metabolic mechanisms. The aim of this study is to evauate the effects of exogenous intraperitoneal administration of adiponectin on the survival, intrabdominal adhesion and inflammatory cytokine levels in an experimental sepsis model. Animal experimentation. Ninety rats were divided into a control group, adiponectin group and sham group. A cecal puncture abdominal sepsis model was performed in the adiponectin and control groups. Every three hours, exogenous adiponectin was administrated to the adiponectin group. At the 3(rd) and 24(th) hours, 10 rats were sacrified in each group in order to measure plasma tumor necrosis factor-α (TNF-α), interleukin (IL) 10, soluble intracellular adhesion molecule (ICAM)-1, IL-6 and macrophage inhibitory factor levels, and the activity of nuclear factor (NF)-kB. The remaining rats were followed for survival. The plasma levels of TNF-α, soluable ICAM-1, IL-6, and macrophage inhibitory factor were significantly higher in the control group than in the adiponectin and sham group (p<0.05). The increase in inflammatory cytokines with time was more prominent in the control group. The activity of NF-kB in the control group was higher than in the adiponectin group (p<0.05). The survival rate of the adiponectin group was higher than in the control group. Administration of exogenous adiponectin to the peritoneum in abdominal sepsis increased survival and decreased intrabdominal adhesions by decreasing the inflammatory response.

The H1-Receptor Antagonist Cetirizine Protects Partially Against Cytokine- and Hydrogen Peroxide–Induced β-TC6 Cell Death In Vitro

It has been proposed that the histamine 1 (H(1)) receptor not only promotes allergic reactions but also modulates autoimmune diseases, such as type 1 diabetes. In line with this, it has recently been reported that the H(1)-receptor antagonist cetirizine can counteract the activation of signals/factors pertinent to the pathogenesis of type 1 diabetes and cytokine-induced β-cell destruction. Therefore, the overall aim of this study was to determine whether H(1)-receptor antagonists affect cytokine-induced β-cell death and signaling in vitro. The insulin-producing cell line β-TC6 was exposed to the proinflammatory cytokines interleukin 1β(+) interferon γ, or hydrogen peroxide. The H(1)-receptor antagonists desloratadine and cetirizine were added to the cell cultures and cell viability; macrophage inhibitory factor levels, c-Jun N-terminal kinase phosphorylation, c-Jun expression, and β-catenin levels were analyzed by flow cytometry, real-time polymerase chain reaction, and immunoblotting. Cetirizine protected partially against both cytokine- and hydrogen peroxide-induced cell death. This effect was paralleled by an inhibition of cytokine-induced c-Jun N-terminal kinase phosphorylation, c-Jun induction, and a restoration of macrophage inhibitory factor contents. Cetirizine also increased the β-TC6 cell contents of β-catenin at basal conditions. Our results indicate a protective effect of a specific H(1)-receptor antagonist.

The Investigation Of Relationship Between Joint Findings and Serum Angiogenic and Inflammatory Factor Levels In Severe Hemophilia A Patients

Despite the use of early prophylactic Factor VIII replacement in severe hemophilia A patients, bleeding into joints cannot be prevented completely and permanent joint damage remains to occur as a result. Early diagnosis and treatment of the joint bleeedings are important for prevention of permanent joint damage. Today, the early detection of the joint bleeding at the beginning of the episode is not possible with clinical signs and current laboratory and radiologic imaging methods. Recent studies have shown that neoangiogenesis plays an important role in development of synovitis after recurrent joint bleedings and the histological abnormalities and findings of neoangiogenesis in hemophiliac arthropathy are similar to those in other joint diseases. This study aimed to investigate the relationship between joint findings and levels of plasma angiogenic and inflammatory factors in severe hemophilia A patients.Severe, inhibitor negative, hemophilia A patients from four hemophilia centers were included into the study. The patient groups consisted of 10 severe hemophilia A patients with acute joint bleeding and joint damage and 25 severe hemophilia A patients with no acute joint bleeding (with or without joint damage). The control group consisted of 22 healthy male children. Each group of patients were further subdivided into two groups with respect to degree of joint damage as presence of mild or severe joint damage. Complete blood count analysis, C-reactive protein (CRP), serum ferritin, lactic acid and ELISA based detection of vascular endhotelial growth factor (VEGF), intercellular adhesion molecule-1, thrombomodulin (TM), macrophage inhibitory factor (MIF), and endostatin levels were detected from the peripheral blood samples of the patient and the control groups. The joint findings of hemophilia A patients were evaluated clinically by hemophilia joint health score and radiologically by Petterson scoring and Denver magnetic resonance imaging scoring methods.Serum ferritin, CRP, and lactic acid levels were found to be increased in hemophilia A patients compared to the control group. CRP was significantly increased in hemophilia patients with joint damage compared to hemophiliacs without joint damage. The increase in levels of CRP and MIF were detected significantly higher in patients with acute joint bleeding. There was a positive correlation between serum TM,VEGF, and MIF levels.The finding of increased levels of CRP and MIF in acute bleeding period supports the presence of bleeding, regardless of the degree of the joint damage. The present findings show that investigation of the levels of these angiogenic factors in large number of severe hemophilia A patients with acute bleeding episodes may give further information about early joint damage. Disclosures:No relevant conflicts of interest to declare.

Candidate gene case-control and functional study shows macrophage inhibitory factor (MIF) polymorphism is associated with cutaneous leishmaniasis

American tegumentary leishmaniasis (ATL) is an infectious disease caused mostly by Leishmania(Viannia)braziliensis in Southeast Brazil. The clinical manifestations are vast, ranging from asymptomatic to severe mucosal leishmaniasis (ML). It has been suggested that variation of the pathogen does not fully explain the response spectrum and the variability of clinical manifestations. Previous data have shown that host genetics also play a role in disease outcome. Herein, we have tested the association of TNF, IL10, IL12 and MIF single nucleotide polymorphisms (SNPs) using a case-control study design including 110 cutaneous leishmaniasis (CL) patients and 682 healthy subjects. The genotype–phenotype correlation was also assessed using leishmania antigens to stimulate peripheral blood mononuclear cells obtained from cured CL patients. Results demonstrated that the MIF −173C allele is associated with leishmaniasis outcome and also with lower levels of MIF in culture supernatants. Also, the TNF −308AA genotype was statistically increased among leishmaniasis patients. The results showed here suggest that the lower levels of MIF produced by MIF −173C carriers could influence the host–Leishmania interaction, favoring infection and disease progression. On the other hand, high TNF levels can contribute to tissue damage, consequently leading to skin lesions.

Microarray-based Transcriptional and Epigenetic Profiling of Matrix Metalloproteinases, Collagens, and Related Genes in Cancer

Epigenetic parameters (DNA methylation, histone modifications, and miRNAs) play a significant role in cancer. To identify the common epigenetic signatures of both the individual matrix metalloproteinases (MMPs) and the additional genes, the function of which is also linked to proteolysis, migration, and tumorigenesis, we performed epigenetic profiling of 486 selected genes in unrelated non-migratory MCF-7 breast carcinoma and highly migratory U251 glioma cells. Genome-wide transcriptional profiling, quantitative reverse transcription-PCR, and microRNA analyses were used to support the results of our epigenetic studies. Transcriptional silencing in both glioma and breast carcinoma cells predominantly involved the repressive histone H3 Lys-27 trimethylation (H3K27me3) mark. In turn, epigenetic stimulation was primarily performed through a gain in the histone H3 Lys-4 dimethylation (H3K4me2) and H3 hyperacetylation and by a global reduction of H3K27me3. Inactive pro-invasive genes in MCF-7 cells but not in U251 cells frequently exhibited a stem cell-like bivalent mark (enrichment in both H3K27me3 and H3K4me2), a characteristic of developmental genes. In contrast with other MMPs, MMP-8 was epigenetically silenced in both cell types, thus providing evidence for the strict epigenetic control of this anti-tumorigenic proteinase in cancer. Epigenetic stimulation of multiple collagen genes observed in cultured glioma cells was then directly confirmed using orthotopic xenografts and tumor specimens. We suggest that the epigenetic mechanisms allow gliomas to deposit an invasion-promoting collagen-enriched matrix and then to use this matrix to accomplish their rapid migration through the brain tissue.

Macrophage migration inhibitory factor and hypothalamo-pituitary-adrenal function during critical illness.

In patients with septic shock (n = 32), multitrauma (n = 8), and hospitalized matched controls (n = 41), we serially measured serum macrophage inhibitory factor (MIF), cortisol, plasma ACTH, tumor necrosis factor-alpha, and interleukin-6 (IL-6) immunoreactivity during 14 days or until discharge/death. MIF levels were significantly elevated on day 1 in septic shock (14.3 +/- 4.5 microg/L), as opposed to trauma (3.1 +/- 1.7 microg/L) and control patients (2.5 +/- 2.1 microg/L). The time course of MIF, parallel to cortisol, but in contrast to ACTH, showed persistently elevated levels in septic patients. On admission, nonsurvivors of septic shock (n = 11) showed significantly higher MIF levels than survivors (18.4 +/- 4.8 and 10.2 +/- 4.2 microg/L, respectively). Patients with septic adult respiratory distress syndrome (ARDS; n = 8) showed higher MIF levels than those who did not develop ARDS (19.4 +/- 4.7 vs. 9.2 +/- 4.3 microg/L, respectively). Multiple logistic regression analysis demonstrated that both MIF and ARDS were independent predictors of adverse outcome. On admission, tumor necrosis factor-alpha, IL-6, procalcitonin, and lipopolysaccharide-binding protein levels were higher in patients with septic shock than in patients with multitrauma. In septic patients, regression analysis showed significant correlations between MIF and cortisol as well as between MIF and IL-6 levels and disease severity scores. No relation was found between MIF and markers of the acute phase response (procalcitonin, C- reactive protein, and lipopolysaccharide-binding protein). In multitrauma patients, MIF levels were not elevated at any time point and were not related to other variables. Our data suggest that during immune-mediated inflammation (such as septic shock) MIF is an important neuroendocrine mediator: a contraregulator of the immunosuppressive effects of glucocorticoids.