ABSTRACT
BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). OBJECTIVE: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. METHODS: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. RESULTS: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = -0.113%, 95% confidence interval (CI): -0.204% to -0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. CONCLUSIONS: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect.
Subject(s)
Central Nervous System Diseases , Macrophage Migration-Inhibitory Factors , Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis , Female , Humans , Male , Atrophy/pathology , Brain/diagnostic imaging , Brain/pathology , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/therapeutic use , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/drug therapy , Multiple Sclerosis, Chronic Progressive/diagnostic imaging , Multiple Sclerosis, Chronic Progressive/drug therapy , Multiple Sclerosis, Chronic Progressive/pathologyABSTRACT
BACKGROUND: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate and adaptive immune systems and in neuroprotection and has recently been implicated in multiple sclerosis (MS). OBJECTIVES: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct subtypes of MS and the cellular localization of MIF in human brain tissue. METHODS: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS) (n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS cohorts were examined. Cellular distribution of MIF in the human brain was studied using immunochemistry and the newly available OligoInternode database. RESULTS: MIF was significantly decreased in treatment-naïve CIS and RRMS patients compared to HCs but was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly lower in women with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes, and oligo5 oligodendrocytes but not in microglia. CONCLUSION: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor expression that affects the overall MIF signaling in the brain and may represent a protective mechanism that eventually fails.
Subject(s)
Macrophage Migration-Inhibitory Factors , Multiple Sclerosis, Chronic Progressive , Multiple Sclerosis, Relapsing-Remitting , Brain , Female , Humans , Intramolecular Oxidoreductases , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Multiple Sclerosis, Chronic Progressive/cerebrospinal fluid , Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluidABSTRACT
BACKGROUND: The pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified. METHODS: Levels 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). RESULTS: The 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. CONCLUSION: Our 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.
Subject(s)
Brain Diseases/immunology , Brain Diseases/pathology , Cytokines/analysis , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Chemokines/analysis , Chemokines/blood , Chemokines/cerebrospinal fluid , Child, Preschool , Cytokines/blood , Cytokines/cerebrospinal fluid , Encephalitis/cerebrospinal fluid , Female , Humans , Infant , Intramolecular Oxidoreductases/blood , Intramolecular Oxidoreductases/cerebrospinal fluid , Leukemia Inhibitory Factor/blood , Leukemia Inhibitory Factor/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/blood , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Male , Osteopontin/blood , Osteopontin/cerebrospinal fluid , Seizures/etiology , Seizures, Febrile/complications , Seizures, Febrile/immunology , Seizures, Febrile/pathologyABSTRACT
BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine. Chronic inflammation induced by amyloid ß proteins (Aß) is one prominent neuropathological feature in Alzheimer's disease (AD) brain. METHODS: Elisa, Western blot, and immunohistochemical staining analysis were performed to examine the level of MIF protein in CSF and brain tissues. MTT and LDH assays were used to examine the neurotoxicity, and the Morris Water Maze test was performed to examine the cognitive function in the MIF+/-/APP23 transgenic mice. RESULTS: MIF expression was upregulated in the brain of AD patients and AD model mice. Elevated MIF concentration was detected in the cerebrospinal fluid of AD patients but not in that of the patients suffering from mild cognitive impairment and vascular dementia. Reduced MIF expression impaired learning and memory in the AD model mice. MIF expression largely associates with Aß deposits and microglia. The binding assay revealed a direct association between MIF and Aß oligomers. Neurons instead of glial cells were responsible for the secretion of MIF upon stimulation by Aß oligomers. In addition, overexpression of MIF significantly protected neuronal cells from Aß-induced cytotoxicity. CONCLUSION: Our study suggests that neuronal secretion of MIF may serve as a defense mechanism to compensate for declined cognitive function in AD, and increased MIF level could be a potential AD biomarker.
Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , Intramolecular Oxidoreductases/biosynthesis , Macrophage Migration-Inhibitory Factors/biosynthesis , Up-Regulation/physiology , Adult , Aged , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnostic imaging , Animals , Biomarkers/cerebrospinal fluid , Biomarkers/metabolism , Female , Humans , Intramolecular Oxidoreductases/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Male , Maze Learning/physiology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Middle AgedABSTRACT
Glucocorticoid (GC) refractory relapses in patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS), who are in potential need of treatment escalation, are a key challenge in routine clinical practice. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be an endogenous counter-regulator of GC, and potentiates autoimmune-mediated neuroinflammation. In order to evaluate whether MIF levels are elevated in the cerebrospinal fluid (CSF) of MS patients (CSF-MIF), and whether they are higher still during a GC refractory relapse, we compared CSF-MIF concentrations of CIS/MS patients with acute optic neuritis as their first inflammatory episode (ON, n = 20), CIS/MS patients with a stable disease progression/without relapse (CIS/MS w/o, n = 18), and healthy controls (HC, n = 20) using ANOVA. Mean CSF-MIF concentrations in CIS/MS w/o patients were significantly higher than in ON patients and HCs, whereas ON patients and HCs did not differ. A subgroup analysis of the ON group revealed 10 patients to be responsive to GC-treatment (GC-ON) and 10 patients refractory under GC-treatment (rGC-ON). However, mean CSF-MIF concentrations did not differ between GC-ON and rGC-ON cases. We therefore conclude that MIF is not suitable for distinguishing GC responders from non-responders in a group of patients with acute optic neuritis, but it rather mirrors the ongoing inflammation in long-term MS disease progression.
Subject(s)
Glucocorticoids/therapeutic use , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Multiple Sclerosis/complications , Optic Neuritis/complications , Optic Neuritis/drug therapy , Adolescent , Adult , Aged , Biomarkers/cerebrospinal fluid , Female , Humans , Male , Middle Aged , Optic Neuritis/cerebrospinal fluid , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein playing a regulatory role in the immune response. First evidence from in vitro and animal studies suggests that MIF may be involved in the development of Alzheimer's disease (AD) pathology. OBJECTIVE: To address in older subjects (i) the relationships between AD pathology and MIF plasma and cerebrospinal fluid (CSF) levels; and (ii) to investigate whether increased MIF-related systemic and CNS inflammation is associated with clinical disease progression. METHODS: CSF and plasma concentrations of MIF as well as biomarkers of amyloid, neuronal injury, and tau hyperphosphorylation (CSF Aß1-42, tau, and ptau, respectively) were assessed in 97 subjects with MCI or mild dementia (cognitive impairment, CI) and 52 healthy volunteers with normal cognition. Clinical and neuropsychological evaluations were performed at inclusion and at follow up visits. RESULTS: CSF MIF levels were higher in participants with CI with an AD CSF biomarker profile, but not in CI with a non-AD profile, compared to the healthy controls. Higher MIF CSF levels were associated with higher CSF tau and ptau and lower CSF Aß1-42 after adjusting for potential confounders. In CI, MIF CSF independently predicted cognitive decline at a follow-up visit after controlling for potential confounders including CSF Aß1-42 and tau levels. CONCLUSION: Our study provides evidence that MIF-related inflammation is related to amyloid pathology, tau hyperphosphorylation, and neuronal injury at the early clinical stages of AD. Higher MIF CSF levels are associated with accelerated cognitive decline in MCI and mild dementia.
Subject(s)
Cognitive Dysfunction/cerebrospinal fluid , Dementia/cerebrospinal fluid , Intramolecular Oxidoreductases/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Aged , Aged, 80 and over , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/cerebrospinal fluid , Apolipoproteins E/genetics , Cognitive Dysfunction/blood , Cognitive Dysfunction/genetics , Cognitive Dysfunction/physiopathology , Dementia/blood , Dementia/genetics , Dementia/physiopathology , Female , Humans , Intramolecular Oxidoreductases/blood , Macrophage Migration-Inhibitory Factors/blood , Male , Middle Aged , Neuropsychological Tests , Peptide Fragments/blood , Peptide Fragments/cerebrospinal fluid , Psychiatric Status Rating Scales , tau Proteins/blood , tau Proteins/cerebrospinal fluidABSTRACT
BACKGROUND: Host factors determining the clinical presentation of tick-borne encephalitis (TBE) are not fully elucidated. The peripheral inflammatory response to TBE virus is hypothesized to facilitate its entry into central nervous system by disrupting the blood-brain barrier with the involvement of a signaling route including Toll-like receptor 3 (TLR3) and pro-inflammatory cytokines macrophage migration inhibitory factor (MIF), tumor necrosis factor-α (TNFα), and interleukin-1 beta (IL-1ß). METHODS: Concentrations of MIF, TNFα, and IL-1ß were measured with commercial ELISA in serum and cerebrospinal fluid (CSF) from 36 hospitalized TBE patients, 7 patients with non-TBE meningitis, and 6 controls. The CSF albumin quotient (AQ) was used as a marker of blood-brain barrier permeability. Single nucleotide polymorphisms rs3775291, rs5743305 (associated with TLR3 expression), and rs755622 (associated with MIF expression) were assessed in blood samples from 108 TBE patients and 72 non-TBE controls. The data were analyzed with non-parametric tests, and p < 0.05 was considered significant. RESULTS: The median serum and CSF concentrations of MIF and IL-1ß were significantly increased in TBE group compared to controls. MIF concentration in serum tended to correlate with AQ in TBE, but not in non-TBE meningitis. The serum concentration of TNFα was increased in TBE patients bearing a high-expression TLR3 rs5743305 TT genotype, which also associated with the increased risk of TBE. The low-expression rs3775291 TLR3 genotype TT associated with a prolonged increase of CSF protein concentration. The high-expression MIF rs755622 genotype CC tended to correlate with an increased risk of TBE, and within TBE group, it was associated with a mild presentation. CONCLUSIONS: The results point to the signaling route involving TLR3, MIF, and TNFα being active in TBE virus infection and contributing to the risk of an overt neuroinvasive disease. The same factors may play a protective role intrathecally contributing to the milder course of neuroinfection. This suggests that the individual variability of the risk and clinical presentation of TBE might be traced to the variable peripheral and intrathecal expression of the mediators of the inflammatory response, which in turn associates with the host genetic background.
Subject(s)
Encephalitis, Tick-Borne/blood , Encephalitis, Tick-Borne/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/blood , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Adolescent , Adult , Aged , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Encephalitis, Tick-Borne/diagnosis , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: Neurosyphilis (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. METHODS: We 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. RESULTS: NS 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. CONCLUSIONS: CSF MIF concentrations can be used as a novel CSF marker to establish or exclude a diagnosis of NS.
Subject(s)
HIV Seronegativity , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Neurosyphilis/cerebrospinal fluid , Neurosyphilis/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/cerebrospinal fluid , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
Pneumococcal meningitis is the most frequent and critical type of bacterial meningitis. Because cytokines play an important role in the pathogenesis of bacterial meningitis, we examined whether functional polymorphisms of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were associated with morbidity and mortality of pneumococcal meningitis. Two functional MIF promoter polymorphisms, a microsatellite (-794 CATT5-8; rs5844572) and a single-nucleotide polymorphism (-173 G/C; rs755622) were genotyped in a prospective, nationwide cohort of 405 patients with pneumococcal meningitis and in 329 controls matched for age, gender, and ethnicity. Carriages of the CATT7 and -173 C high-expression MIF alleles were associated with unfavorable outcome (P= 0.005 and 0.003) and death (P= 0.03 and 0.01). In a multivariate logistic regression model, shock [odds ratio (OR) 26.0, P= 0.02] and carriage of the CATT7 allele (OR 5.12,P= 0.04) were the main predictors of mortality. MIF levels in the cerebrospinal fluid were associated with systemic complications and death (P= 0.0002). Streptococcus pneumoniae strongly up-regulated MIF production in whole blood and transcription activity of high-expression MIF promoter Luciferase reporter constructs in THP-1 monocytes. Consistent with these findings, treatment with anti-MIF immunoglogulin G (IgG) antibodies reduced bacterial loads and improved survival in a mouse model of pneumococcal pneumonia and sepsis. The present study provides strong evidence that carriage of high-expression MIF alleles is a genetic marker of morbidity and mortality of pneumococcal meningitis and also suggests a potential role for MIF as a target of immune-modulating adjunctive therapy.
Subject(s)
Intramolecular Oxidoreductases/genetics , Macrophage Migration-Inhibitory Factors/genetics , Meningitis, Pneumococcal/genetics , Polymorphism, Genetic , Adult , Aged , Animals , Antibodies, Neutralizing/administration & dosage , Case-Control Studies , Cell Line , Disease Models, Animal , Female , Genetic Predisposition to Disease , Humans , Intramolecular Oxidoreductases/antagonists & inhibitors , Intramolecular Oxidoreductases/cerebrospinal fluid , Intramolecular Oxidoreductases/immunology , Macrophage Migration-Inhibitory Factors/antagonists & inhibitors , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/immunology , Male , Meningitis, Pneumococcal/cerebrospinal fluid , Meningitis, Pneumococcal/mortality , Mice , Mice, Inbred BALB C , Microsatellite Repeats , Middle Aged , Netherlands/epidemiology , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Prospective Studies , Streptococcus pneumoniae/pathogenicityABSTRACT
BACKGROUND: Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. METHODS: A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aß42 was used as a continuous trait in these analyses. RESULTS: The ptau181-Aß42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aß42) compared with elderly control subjects with no pathology (low ptau181, high Aß42). The FABP-Aß42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aß42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD. CONCLUSIONS: Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Aged, 80 and over , Biomarkers/cerebrospinal fluid , Case-Control Studies , Cohort Studies , Disease Progression , Fatty Acid Binding Protein 3 , Fatty Acid-Binding Proteins/cerebrospinal fluid , Female , Humans , Immunoassay/methods , Intramolecular Oxidoreductases/cerebrospinal fluid , Kaplan-Meier Estimate , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Male , Multivariate Analysis , Phosphorylation , Time Factors , Vascular Endothelial Growth Factor A/cerebrospinal fluidABSTRACT
Previous studies have shown that amyloid beta protein (Abeta ), the essential molecule for the formation of toxic oligomers and, subsequently, Alzheimer plaques, has been associated in vivo with the immune modulator, macrophage migration inhibitory factor (MIF) (17). To further investigate this association in vivo we used the APP transgenic mouse model. Serial brain sections of transgenic APP mice were stained for Abeta plaques and MIF and we observed MIF immunolabeling in microglial cells in association with Abeta plaques in the transgenic mouse brain sections. In addition, functional studies in murine and human neuronal cell lines revealed that Abeta-induced toxicity could be reversed significantly by a small molecule inhibitor of MIF (ISO-1). Finally, to elucidate the role of MIF in Alzheimer's Disease (AD) we measured MIF levels in the brain cytosol and cerebrospinal fluid (CSF) of AD patients and age-matched controls. Our results demonstrate a marked increase of MIF levels within the CSF of AD patients compared with controls. Combined, our results indicate a strong role for MIF in the pathogenesis of AD and furthermore suggest that inhibition of MIF may provide a valuable avenue of investigation for the prevention of disease onset, progression and/or severity.
Subject(s)
Alzheimer Disease/metabolism , Intramolecular Oxidoreductases/metabolism , Macrophage Migration-Inhibitory Factors/metabolism , Aged , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Brain/metabolism , Brain Chemistry , Cell Survival/drug effects , Female , Histocytochemistry , Humans , Intramolecular Oxidoreductases/antagonists & inhibitors , Intramolecular Oxidoreductases/cerebrospinal fluid , Isoxazoles/pharmacology , Macrophage Migration-Inhibitory Factors/antagonists & inhibitors , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Male , Mice , Mice, Transgenic , Neuroblastoma , Protease Nexins , Receptors, Cell Surface/genetics , Statistics, Nonparametric , Tumor Cells, CulturedABSTRACT
Pro-inflammatory cytokine production after nociceptive stimuli is pivotal for hyperalgesia. As macrophage migration inhibitory factor (MIF), a pleiotropic cytokine produced mainly by nonneuronal tissue, has been involved in the regulation of neuronal functions, herein we examined the role for MIF in formalin-induced inflammatory pain model. MIF critically contributed to nociceptive behaviors following formalin injection. Specifically, spinal administration of a MIF inhibitor (ISO-1) prevented and reversed flinching responses in rats. Further examination showed that levels of both MIF and the MIF receptor CD74 were substantially increased within the ipsilateral spinal cord dorsal horn after formalin administration. Mechanistic studies revealed that MIF upregulated the expression of the spinal NMDA receptor subunit NR2B via the MAPK signaling pathway. Moreover, microglial cells were found to be the major source of spinal MIF after formalin administration by fluorescence colocalization. These data highlight spinal MIF plays a critical role in the pathogenesis of formalin-induced inflammatory pain and suggest MIF may be a potential target for therapy of such pathological condition.
Subject(s)
Hyperalgesia/etiology , Hyperalgesia/pathology , Inflammation/complications , Intramolecular Oxidoreductases/blood , Intramolecular Oxidoreductases/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/blood , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Spinal Cord/metabolism , Analysis of Variance , Animals , CD47 Antigen/metabolism , Cells, Cultured , Disease Models, Animal , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay/methods , Formaldehyde , Functional Laterality/physiology , Glial Fibrillary Acidic Protein/metabolism , Hyperalgesia/drug therapy , Inflammation/chemically induced , Injections, Spinal/methods , Isoxazoles/pharmacology , Lectins/metabolism , Male , Microglia/drug effects , Microglia/metabolism , Mitogen-Activated Protein Kinase Kinases/metabolism , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Transduction/drug effects , Spinal Cord/drug effects , Up-Regulation/drug effects , tau Proteins/metabolismABSTRACT
Bacterial meningitis is a complex disorder in which injury is caused, in part, by the causative organism and, in part, by the host's own inflammatory response. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine and a neuro-endocrine mediator that might play a role in pneumococcal meningitis. Here, we discuss the role of MIF in infection, the brain, and corticosteroids and conclude that experimental meningitis studies have to determine whether MIF is a potential target for adjunctive therapy in pneumococcal meningitis.
Subject(s)
Adrenal Cortex Hormones/therapeutic use , Encephalitis/immunology , Macrophage Migration-Inhibitory Factors/immunology , Adrenal Cortex Hormones/administration & dosage , Encephalitis/drug therapy , Encephalitis/physiopathology , Humans , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/drug effectsABSTRACT
INTRODUCTION: Macrophage migration inhibitory factor (MIF) plays an essential pathophysiological role in septic shock, but its role in central nervous system infection (CNS) remains to be defined. METHODS: We investigated cerebrospinal fluid (CSF) levels of MIF in 171 patients who were clinically suspected of having meningitis on admission. Of these, 31 were found to have purulent meningitis of known aetiology, 20 purulent meningitis of unknown aetiology, 59 lymphocytic meningitis and 11 encephalitis, whereas 50 were suspected of having but had no evidence of CNS infection. RESULTS: CSF MIF levels were significantly higher in patients with purulent meningitis of known aetiology (median [interquartile range]: 8,639 [3,344 to 20,600] ng/l) than in patients with purulent meningitis of unknown aetiology (2,209 [1,516 to 6,550] ng/l; Mann-Whitney test, P = 0.003), patients with lymphocytic meningitis (1,912 [1,302 to 4,105] ng/l; P < 0.001) and patients suspected of having but without evidence of CNS infection (1,472 [672 to 3,447] ng/l; P < 0.001). Also, patients with encephalitis (6,937 [3,961 to 8,353] ng/l) had higher CSF MIF than did patients without CNS infection (P < 0.01). Among patients with purulent meningitis, CSF MIF levels were significantly higher in patients infected with pneumococci than in those with meningococcal infection (11,569 [8,615 to 21,935] ng/l versus 5,006 [1,717 to 10,905] ng/l; P = 0.02), in patients who required versus those not requiring assisted ventilation (10,493 [5,961 to 22,725] ng/l versus 3,240 [1,563 to 9,302] ng/l; P = 0.003), and in patients with versus those without impaired consciousness (8,614 [3,344 to 20,935] ng/l versus 2,625 [1,561 to 7,530] ng/l; P = 0.02). CSF MIF levels correlated significantly with meningeal inflammation (P < 0.05) but not with systemic inflammatory response (P > 0.05) in patients with purulent meningitis of known aetiology, those with lymphocytic meningitis and those with encephalitis. CONCLUSIONS: MIF was significantly increased in the CSF of patients with purulent meningitis and encephalitis, and was to some degree associated with severity of the infection. Our findings indicate that MIF may play an important role in CNS infection.
Subject(s)
Encephalitis/diagnosis , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Meningitis/diagnosis , Adolescent , Adult , Biomarkers/cerebrospinal fluid , Case-Control Studies , Child , Diagnosis, Differential , Encephalitis/cerebrospinal fluid , Female , Humans , Male , Meningitis/cerebrospinal fluid , Meningitis, Aseptic/cerebrospinal fluid , Meningitis, Aseptic/diagnosis , Meningitis, Bacterial/cerebrospinal fluid , Meningitis, Bacterial/diagnosis , Meningitis, Viral/cerebrospinal fluid , Meningitis, Viral/diagnosis , Middle Aged , Sensitivity and Specificity , Severity of Illness IndexABSTRACT
Inflammatory processes may substantially contribute to the cerebral pathology in Alzheimer's disease (AD) and accelerate the disease progression. The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine which promotes the production of several inflammatory mediators such as TNF-alpha, IL-6 and IFN-gamma, and plays a central regulatory role in the pathogenesis of several inflammatory and autoimmune diseases. There is now first evidence that MIF may be involved in the neuroinflammation in AD. To determine whether MIF production is up-regulated early in the course of AD, we compared the levels of MIF assessed by ELISA in the cerebrospinal fluid (CSF) of 31 patients with AD, 28 patients with amnestic mild cognitive impairment (MCI), and 19 subjects without cognitive deficits. Additionally, we measured the CSF concentrations of the inflammatory mediators TNF-alpha, IL-6 and IFN-gamma, which are thought to be both up-regulated by MIF and involved in the pathophysiology of AD. CSF MIF concentrations were significantly increased in AD (p=0.003) and MCI patients (p<0.001) compared to controls. The levels of TNF-alpha, IL-6 and IFN-gamma did not differ significantly between the groups. There was a correlation only between the concentrations of MIF and of TNF-alpha in the AD group (r=0.407; p=0.023). These results demonstrate increased MIF production in AD and MCI suggesting that MIF may be involved in the occurring neuroinflammatory process at a clinical pre-dementia disease stage.
Subject(s)
Alzheimer Disease/immunology , Cognition Disorders/immunology , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Aged , Aged, 80 and over , Alzheimer Disease/cerebrospinal fluid , Cognition Disorders/cerebrospinal fluid , Enzyme-Linked Immunosorbent Assay , Female , Humans , Interferon-gamma/cerebrospinal fluid , Interleukin-6/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/immunology , Male , Middle Aged , Severity of Illness Index , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Up-RegulationABSTRACT
Macrophage migration inhibitory factor (MIF) is becoming increasingly recognized as an important regulator of immune and inflammatory responses. It is released by activated T lymphocytes and macrophages and up-regulates the proinflammatory activity of these cells. MIF is required for antigen- and mitogen-driven T cell activation, and stimulates macrophages to release cytokines and nitric oxide. On the basis of the recent suggestion that pharmacological modulation of MIF production and neutralization of its activity may have important implications for treatment of a variety of autoimmune or inflammatory conditions, we determined the level of MIF in the cerebrospinal fluid (CSF) of patients with conventional-form multiple sclerosis (C-MS) and optic-spinal form multiple sclerosis (OpS-MS), and neuro-Behçet's disease (NBD). As control, the CSF of patients with non-inflammatory neurological diseases (NIND) was used. The concentration of MIF in CSF samples was significantly elevated in relapsed cases of C-MS (4.13+/-1.07 ng/ml) (mean+/-S.D.) compared with control samples (2.38+/-0.60 ng/ml) (P<0.0001), whereas MIF in the CSF of C-MS patients in remission was not elevated (2.65+/-0.67 ng/ml). The concentration of MIF in the CSF of OpS-MS patients in relapse (5.53+/-1.74 ng/ml) was higher than that of patients with C-MS in relapse (P<0.05). In NBD patients, the concentration of MIF in CSF was significantly elevated (7.47+/-5.61 ng/ml) compared with control samples (P<0.01) and correlated well with cell count in these samples (r=0.910, P<0.005). These results suggest that MIF may play a pivotal role in immune-mediated diseases of the central nervous system, and that MIF may be useful in the study of differences between C-MS and OpS-MS.
Subject(s)
Behcet Syndrome/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Multiple Sclerosis/cerebrospinal fluid , Optic Nerve Diseases/cerebrospinal fluid , Spinal Cord Diseases/cerebrospinal fluid , Adolescent , Adult , Behcet Syndrome/immunology , Behcet Syndrome/physiopathology , Child , Female , Humans , Male , Middle Aged , Multiple Sclerosis/immunology , Multiple Sclerosis/physiopathology , Optic Nerve Diseases/etiology , Optic Nerve Diseases/immunology , Spinal Cord Diseases/etiology , Spinal Cord Diseases/immunologyABSTRACT
Macrophage migration inhibitory factor (MIF) has been rediscovered as a hormone and immunomodulator as well as a proinflammatory cytokine. We investigated the expression of MIF protein and mRNA in the rat brain using optimized immunohistochemistry and in situ hybridization, respectively. By immunohistochemical analysis, we found that MIF protein was present in the epithelial cells of the choroid plexus and ependymal cells as well as astrocyte-like cells in the cerebral white matter and cortex. Tissue sections double-stained for glial fibrillary acidic protein (GFAP) and MIF revealed the presence of MIF protein in astrocytes, whereas this protein was scarcely identified in the neurons by staining using an anti-MIF antibody. We also measured the MIF content in the cerebrospinal fluid, which was 15.5 +/- 2.5 ng/ml (mean +/- SEM), comparable to the serum MIF value. In contrast, expression of MIF mRNA was found not only in astrocytes but also in neurons by the in situ hybridization technique. These results suggest that MIF plays a pivotal role as an immunomodulatory cytokine for inflammatory reactions and immune responses in the whole central nervous system.
Subject(s)
Brain/cytology , In Situ Hybridization , Macrophage Migration-Inhibitory Factors/analysis , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Animals , Blotting, Northern , Choroid Plexus/chemistry , Choroid Plexus/cytology , Enzyme-Linked Immunosorbent Assay , Epithelial Cells/chemistry , Epithelial Cells/cytology , Frontal Lobe/chemistry , Frontal Lobe/cytology , Glial Fibrillary Acidic Protein/analysis , Immunohistochemistry , Kidney/chemistry , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/genetics , Male , Rats , Rats, Inbred F344ABSTRACT
BACKGROUND: The mediator known historically as macrophage migration inhibitory factor (MIF) has been identified recently as being released into the circulation by the anterior pituitary gland as a consequence of stress or during a systemic inflammatory response. Macrophages and T cells also secrete MIF, both in response to proinflammatory factors or upon stimulation with glucocorticoids. Once released, MIF "overrides" or counterregulates the immunosuppressive effects of steroids on cytokine production and immune cellular activation. To further investigate the biology of MIF and its role in the neuroendocrine system, we have studied the regional and cellular expression of MIF in brain tissue obtained from normal rats and rats administered LPS intracisternally. MATERIALS AND METHODS: Rat brain sections were analyzed by immunohistochemistry utilizing an affinity-purified, anti-MIF antibody raised to recombinant MIF, and by in situ hybridization using a digoxigenin-labeled, antisense MIF cRNA probe. The kinetics of MIF mRNA expression in brain were compared with that of IL-1, IL-6, and TNF-alpha by RT-PCR of total brain RNA. The cerebrospinal fluid content of MIF and TNF-alpha proteins was analyzed by Western blotting and ELISA. RESULTS: A strong baseline expression pattern for MIF was observed in neurons of the cortex, hypothalamus, hippocampus, cerebellum, and pons. By in situ hybridization, MIF mRNA was found predominantly in cell bodies whereas MIF protein was detected mostly within the terminal fields associated with neurons. There was a marked pattern of MIF immunoreactivity within the mossy fibers of the dentate gyrus and dendrites of the hippocampal CA3 field. These structures have been shown previously to be involved in glucocorticoid-induced tissue damage within the hippocampus, suggesting an association between MIF and targets of glucocorticoid action. The intracisternal injection of LPS increased MIF mRNA and protein expression in brain and MIF immunoreactivity was due in part to infiltrating monocytes/macrophages. MIF protein also was found to be rapidly released into the cerebrospinal fluid. This response corresponded with that of LPS-induced cytokine release and MIF mRNA expression increased in a distribution that colocalized in large part with that of TNF-alpha, IL-1 beta, and IL-6. CONCLUSION: The significant levels of baseline and inducible MIF expression in the brain and its regional association with glucocorticoid action underscore the importance of this mediator as a physiological regulator of the inflammatory stress response and further define its role within the neuroendocrine system.
Subject(s)
Brain Chemistry , Macrophage Migration-Inhibitory Factors/analysis , Neurons/chemistry , Animals , Interleukin-1/genetics , Interleukin-6/genetics , Lipopolysaccharides/pharmacology , Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Macrophage Migration-Inhibitory Factors/genetics , Macrophages , Male , Monocytes/chemistry , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Tumor Necrosis Factor-alpha/geneticsABSTRACT
BACKGROUND: Among spinal cord injuries, secondary injury is considered to be a "reversible" process and seems to be a key target for the treatment of spinal cord injury. Recently, macrophage migration inhibitory factor (MIF) has been reevaluated as being one of the most important cytokines which act during wound healing, proliferation and differentiation of cells. However, the expression of MIF in the spinal cord has not been investigated yet. PURPOSE: The purpose of this paper is to demonstrate the MIF expression in normal rat spinal cord and to evaluate the kinetics of MIF after spinal cord injury. MATERIALS & METHODS: Female Wistar (280-320 g) rats were studied. Spinal cord injury was made by the clip compression method at the level of C7/Th1 (56 g, For 1 min.). The expression of MIF was examined by immunohistochemistry and northern blot analysis. MIF content in the cerebrospinal fluid (CSF) was measured by enzyme-linked immunosorbent assays (ELISA). Furthermore, to examine the MIF function on neuronal cell, cell proliferation assay (MTS assay) was carried out using PC12, pheochromocytoma cell line, and LN444, glioblastoma cell line, in the presence of anti-MIF monoclonal antibody. RESULTS: MIF stain was positive in normal rat spinal cord white matter. The expression of MIF decreased between 1 hour and 6 hours after injury. It was found to have re-appeared 24 hours after injury. The kinetics of MIF mRNA expression showed reverse-correlation with those of the MIF positive stain. MIF content in CSF was found to be elevated soon after injury. MTS assay suggested that MIF had some proliferative function on neuronal cells. CONCLUSION: MIF exists in the rat white matter. And it's immediately released into the CSF and then re-synthesized 24-hr after injury. MIF shows a cell proliferative function on neuronal cells. These results suggest that MIF plays an important role for secondary spinal cord injury.
Subject(s)
Macrophage Migration-Inhibitory Factors/cerebrospinal fluid , Spinal Cord Injuries/metabolism , Animals , Cell Division , Cells, Cultured , Female , Macrophage Migration-Inhibitory Factors/physiology , Neurons/cytology , Rats , Rats, WistarABSTRACT
Inhibition of electrophoretic cell migration using cerebrospinal fluid (CSF) directly was investigated by the modified MEM (macrophage electrophoretic mobility) and TEEM (tanned sheep erythrocyte electrophoretic mobility) tests, respectively. An inhibitory activity of macrophage slowing factor (MSF)--one of in vivo lymphokines--in CSF was established in cases of multiple sclerosis (17.5 +/- 3.8%), and neurolues. The value of this MSF assay turned out to be significantly different from the remaining inflammatory ailments of the nervous system (10.1 +/- 6.8%). Results of other neurological diseases were found to be very much lower (5.1 +/- 4.2%). It seems important, for immunopathogenesis and the diagnosis of neuroimmunological diseases with enhanced cellular immunoreaction, to evaluate MSF activity in CSF. To characterize the active factor in CSF (and serum) these fluids were fractionated by gel filtration chromatography as well as supernatants from lymphocyte-antigen incubation in MS patients. The main activity for inhibition of electrophoretic cell mobility was eluated in the same fraction in these fluids. It could be shown that units have a molecular weight of about 15000 Daltons; this value for MSF lies below those for other inhibitory lymphokines.