Showing papers by "Richard Bucala published in 2013"
TL;DR: This review addresses the current knowledge of the actions of pro- and anti-inflammatory cytokines in sepsis pathophysiology as well as how these cytokines and other important immunomodulating agents may be therapeutically targeted to improve the clinical outcome of sepsi.
Abstract: Sepsis and septic shock are among the leading causes of death in intensive care units worldwide. Numerous studies on their pathophysiology have revealed an imbalance in the inflammatory network leading to tissue damage, organ failure, and ultimately, death. Cytokines are important pleiotropic regulators of the immune response, which have a crucial role in the complex pathophysiology underlying sepsis. They have both pro- and anti-inflammatory functions and are capable of coordinating effective defense mechanisms against invading pathogens. On the other hand, cytokines may dysregulate the immune response and promote tissue-damaging inflammation. In this review, we address the current knowledge of the actions of pro- and anti-inflammatory cytokines in sepsis pathophysiology as well as how these cytokines and other important immunomodulating agents may be therapeutically targeted to improve the clinical outcome of sepsis.
579 citations
TL;DR: The role of macrophage migration inhibitory factor (MIF), a cytokine that is encoded in a functionally polymorphic locus in humans, in TB is examined and genetic low expressers of MIF to be enriched in a population of patients with HIV and disseminated TB.
Abstract: Macrophage migration inhibitory factor (MIF), an innate cytokine encoded in a functionally polymorphic genetic locus, contributes to detrimental inflammation but may be crucial for controlling infection. We explored the role of variant MIF alleles in tuberculosis. In a Ugandan cohort, genetic low expressers of MIF were 2.4-times more frequently identified among patients with Mycobacterium tuberculosis (TB) bacteremia than those without. We also found mycobacteria-stimulated transcription of MIF and serum MIF levels to be correlated with MIF genotype in human macrophages and in a separate cohort of US TB patients, respectively. To determine mechanisms for MIF’s protective role, we studied both aerosolized and i.v. models of mycobacterial infection and observed MIF-deficient mice to succumb more quickly with higher organism burden, increased lung pathology, and decreased innate cytokine production (TNF-α, IL-12, IL-10). MIF-deficient animals showed increased pulmonary neutrophil accumulation but preserved adaptive immune response. MIF-deficient macrophages demonstrated decreased cytokine and reactive oxygen production and impaired mycobacterial killing. Transcriptional investigation of MIF-deficient macrophages revealed reduced expression of the pattern recognition receptor dectin-1; restoration of dectin-1 expression recovered innate cytokine production and mycobacterial killing. Our data place MIF in a crucial upstream position in the innate immune response to mycobacteria and suggest that commonly occurring low expression MIF alleles confer an increased risk of TB disease in some populations.
110 citations
TL;DR: A role is identified for EPC-derived proangiogenic MIF, VEGF and MIF receptors in EPC recruitment following hypoxia, EPC differentiation and subsequent tube and vessel formation, whereas CXCL12, a mediator of early EPC recruited cells, does not contribute to the remodeling process.
Abstract: This study aimed to analyze the role of endothelial progenitor cell (EPC)-derived angiogenic factors and chemokines in the multistep process driving angiogenesis with a focus on the recently discovered macrophage migration inhibitory factor (MIF)/chemokine receptor axis. Primary murine and murine embryonic EPCs (eEPCs) were analyzed for the expression of angiogenic/chemokines and components of the MIF/CXC chemokine receptor axis, focusing on the influence of hypoxic versus normoxic stimulation. Hypoxia induced an upregulation of CXCR2 and CXCR4 but not CD74 on EPCs and triggered the secretion of CXCL12, CXCL1, MIF, and vascular endothelial growth factor (VEGF). These factors stimulated the transmigration activity and adhesive capacity of EPCs, with MIF and VEGF exhibiting the strongest effects under hypoxia. MIF-, VEGF-, CXCL12-, and CXCL1-stimulated EPCs enhanced tube formation, with MIF and VEGF exhibiting again the strongest effect following hypoxia. Tube formation following in vivo implantation utilizing angiogenic factor-loaded Matrigel plugs was only promoted by VEGF. Coloading of plugs with eEPCs led to enhanced tube formation only by CXCL12, whereas MIF was the only factor which induced differentiation towards an endothelial and smooth muscle cell (SMC) phenotype, indicating an angiogenic and differentiation capacity in vivo. Surprisingly, CXCL12, a chemoattractant for smooth muscle progenitor cells, inhibited SMC differentiation. We have identified a role for EPC-derived proangiogenic MIF, VEGF and MIF receptors in EPC recruitment following hypoxia, EPC differentiation and subsequent tube and vessel formation, whereas CXCL12, a mediator of early EPC recruitment, does not contribute to the remodeling process. By discerning the contributions of key angiogenic chemokines and EPCs, these findings offer valuable mechanistic insight into mouse models of angiogenesis and help to define the intricate interplay between EPC-derived angiogenic cargo factors, EPCs, and the angiogenic target tissue.
84 citations
TL;DR: Analysis of the early response of wildtype and MIF−/− mice to ethanol indicates that MIF is an important mediator in the regulation of chemokine production and immune cell infiltration in the liver during ethanol feeding and promotes ethanol‐induced steatosis and hepatocyte damage.
67 citations
TL;DR: The pharmacological utility of small-molecule MIF agonists in enhancing AMPK activation and reducing cardiac ischemic injury is supported and the specificity of MIF20 for MIF-dependent AMPK signaling is verified.
Abstract: Background—Macrophage migration inhibitory factor (MIF) exerts a protective effect on ischemic myocardium by activating AMP-activated protein kinase (AMPK). Small molecules that increase the affinity of MIF for its receptor have been recently designed, and we hypothesized that such agonists may enhance AMPK activation and limit ischemic tissue injury. Methods and Results—Treatment of cardiomyocytes with the candidate MIF agonist, MIF20, augmented AMPK phosphorylation, increased by 50% the surface localization of glucose transporter, and enhanced by 25% cellular glucose uptake in comparison with MIF alone. In mouse hearts perfused with MIF20 before no-flow ischemia and reperfusion, postischemic left ventricular function improved commensurately with an increase in cardiac MIF-AMPK activation and an augmentation in myocardial glucose uptake. By contrast, small-molecule MIF agonism was not effective in cells or tissues genetically deficient in MIF or the MIF receptor, verifying the specificity of MIF20 for MI...
66 citations
TL;DR: It is suggested that MIF serves as an indispensable cardioprotective factor against doxorubicin‐induced cardiomyopathy with an underlying mechanism through facilitating autophagolysosome formation.
Abstract: Background Recent evidence has depicted a role of macrophage migration inhibitory factor (MIF) in cardiac homeostasis under pathological conditions. This study was designed to evaluate the role of MIF in doxorubicin-induced cardiomyopathy and the underlying mechanism involved with a focus on autophagy.
Methods and Results Wild-type (WT) and MIF knockout (MIF−/−) mice were given saline or doxorubicin (20 mg/kg cumulative, i.p.). A cohort of WT and MIF−/− mice was given rapamycin (6 mg/kg, i.p.) with or without bafilomycin A1 (BafA1, 3 μmol/kg per day, i.p.) for 1 week prior to doxorubicin challenge. To consolidate a role for MIF in the maintenance of cardiac homeostasis following doxorubicin challenge, recombinant mouse MIF (rmMIF) was given to MIF−/− mice challenged with or without doxorubicin. Echocardiographic, cardiomyocyte function, and intracellular Ca2+ handling were evaluated. Autophagy and apoptosis were examined. Mitochondrial morphology and function were examined using transmission electron microscopy, JC-1 staining, MitoSOX Red fluorescence, and mitochondrial respiration complex assay. DHE staining was used to evaluate reactive oxygen species (ROS) generation. MIF knockout exacerbated doxorubicin-induced mortality and cardiomyopathy (compromised fractional shortening, cardiomyocyte and mitochondrial function, apoptosis, and ROS generation). These detrimental effects of doxorubicin were accompanied by defective autophagolysosome formation, the effect of which was exacerbated by MIF knockout. Rapamycin pretreatment rescued doxorubicin-induced cardiomyopathy in WT and MIF−/− mice. Blocking autophagolysosome formation using BafA1 negated the cardioprotective effect of rapamycin and rmMIF.
Conclusions Our data suggest that MIF serves as an indispensable cardioprotective factor against doxorubicin-induced cardiomyopathy with an underlying mechanism through facilitating autophagolysosome formation.
64 citations
TL;DR: A recently completed candidate gene association study in the autoimmune disease systemic lupus erythematosus (SLE) indicates that individuals with a high-expression MIF allele have reduced incidence of SLE, and results support the clinical feasibility of pharmacologic MIF antagonism as such therapies may be most effectively applied in those individuals who manifest a MIF dependent form of autoimmunity.
Abstract: Macrophage migration inhibitory factor (MIF) is an innate cytokine whose main actions include counter-regulating the immunosuppressive action of glucocorticoids and inhibiting activation-induced apoptosis. MIF is encoded in a functionally polymorphic locus and human genetic studies have shown significant relationships between high-expression MIF alleles, host inflammatory responses, and improved clinical outcome from infections. A recently completed candidate gene association study in the autoimmune disease systemic lupus erythematosus (SLE) indicates that individuals with a high-expression MIF allele have reduced incidence of SLE. Among patients with established disease however, those with end-organ complications have increased frequency of high-expression MIF alleles. Plasma MIF levels and Toll-like receptor (TLR) stimulated MIF production also reflect the underlying MIF genotype. These data suggest that MIF exerts a dual influence on the immunopathogenesis of SLE: high-expression MIF alleles are associated with a reduced susceptibility to SLE, perhaps by enhancing clearance of autoimmunogenic pathogens; once SLE develops however, low-expression MIF alleles protect from ensuing inflammatory end-organ damage. These data thus provide an example of the potential evolutionary advantage of maintaining an autoimmunity susceptibility gene in the population in that high-expression MIF alleles may allow for a maximal anti-infective response despite risk of autoimmunity. These results also support the clinical feasibility of pharmacologic MIF antagonism as such therapies may be most effectively applied in those individuals who, on the basis of their genotype, manifest a MIF dependent form of autoimmunity.
64 citations
TL;DR: The MIF gene and protein are associated with RA in a western Mexican population, with a main contribution onto early onset and early stages of disease.
57 citations
TL;DR: Although MIF confers protective effects by improving myocardial healing and function through CXCR2 in resident cells, thereby complementing paracrine effects through CD74/AMP-activated protein kinase, it exerts detrimental effects on CxCR2-bearing inflammatory cells by increasing monocyte infiltration and impairing heart function.
Abstract: Objective— Here, we aimed to clarify the role of CXC chemokine receptor (CXCR) 2 in macrophage migration-inhibitory factor (MIF)–mediated effects after myocardial ischemia and reperfusion. As a pleiotropic chemokine-like cytokine, MIF has been identified to activate multiple receptors, including CD74 and CXCR2. In models of myocardial infarction, MIF exerts both proinflammatory effects and protective effects in cardiomyocytes. Similarly, CXCR2 displays opposing effects in resident versus circulating cells. Approach and Results— Using bone marrow transplantation, we generated chimeric mice with Cxcr2 −/− bone marrow–derived inflammatory cells and wild-type (wt) resident cells (wt/Cxcr2 −/− ), Cxcr2 −/− cardiomyocytes and wt bone marrow–derived cells (Cxcr2 −/− /wt), and wt controls reconstituted with wt bone marrow (wt/wt). All groups were treated with anti-MIF or isotype control antibody before they underwent myocardial ischemia and reperfusion. Blocking MIF increased infarction size and impaired cardiac function in wt/wt and wt/CXCR2 −/− mice but ameliorated functional parameters in Cxcr2 −/− /wt mice, as analyzed by echocardiography and Langendorff perfusion. Neutrophil infiltration and angiogenesis were unaltered by MIF blockade or Cxcr2 deficiency. Monocyte infiltration was blunted in wt/Cxcr2 −/− mice and reduced by MIF blockade in wt/wt and Cxcr2 −/− /wt mice. Furthermore, MIF blockade attenuated collagen content in all groups in a CXCR2-independent manner. Conclusions— The compartmentalized and opposing effects of MIF after myocardial ischemia and reperfusion are largely mediated by CXCR2. Although MIF confers protective effects by improving myocardial healing and function through CXCR2 in resident cells, thereby complementing paracrine effects through CD74/AMP-activated protein kinase, it exerts detrimental effects on CXCR2-bearing inflammatory cells by increasing monocyte infiltration and impairing heart function. These dichotomous findings should be considered when developing novel therapeutic strategies to treat myocardial infarction.
54 citations
TL;DR: Results indicate that MIF plays a permissive role in the maintenance of cardiac contractile function under starvation by regulation of autophagy.
Abstract: Aims The cytokine macrophage migration inhibitory factor (MIF) protects the heart through AMPK activation. Autophagy, a conserved pathway for bulk degradation of intracellular proteins and organelles, helps preserve and recycle energy and nutrients for cells to survive under starvation. This study was designed to examine the role of MIF in cardiac homeostasis and autophagy regulation following an acute starvation challenge.
Methods and results Wild-type (WT) and MIF knockout mice were starved for 48 h. Echocardiographic data revealed little effect of starvation on cardiac geometry, contractile and intracellular Ca2+ properties. MIF deficiency unmasked an increase in left ventricular end-systolic diameter, a drop in fractional shortening associated with cardiomyocyte contractile and intracellular Ca2+ anomalies following starvation. Interestingly, the unfavourable effect of MIF deficiency was associated with interruption of starvation-induced autophagy. Furthermore, restoration of autophagy using rapamycin partially protected against starvation-induced cardiomyocyte contractile defects. In our in vitro model of starvation, neonatal mouse cardiomyocytes from WT and MIF−/− mice and H9C2 cells were treated with serum free-glucose free DMEM for 2 h. MIF depletion dramatically attenuated starvation-induced autophagic vacuole formation in neonatal mouse cardiomyocytes and exacerbated starvation-induced cell death in H9C2 cells.
Conclusion In summary, these results indicate that MIF plays a permissive role in the maintenance of cardiac contractile function under starvation by regulation of autophagy.
50 citations
TL;DR: In this article, partial MHC class II constructs comprised of linked β1α1 domains with covalently attached antigenic peptides (also referred to as recombinant T-cell receptor ligands - RTLs) were shown to inhibit MIF activity by not only blocking the binding of rhMIF to immunopurified CD74, but also down-regulating CD74 cell-surface expression.
Abstract: Macrophage migration inhibitory factor (MIF) and its receptor, CD74, are pivotal regulators of the immune system. Here we demonstrate for the first time that partial MHC class II constructs comprised of linked β1α1 domains with covalently attached antigenic peptides (also referred to as recombinant T-cell receptor ligands - RTLs) can inhibit MIF activity by not only blocking the binding of rhMIF to immunopurified CD74, but also down-regulating CD74 cell-surface expression. This bi-functional inhibition of MIF/CD74 interactions blocked downstream MIF effects, including enhanced secretion of proinflammatory cytokines, anti-apoptotic activity and inhibition of random migration that all contribute to the reversal of clinical and histological signs of experimental autoimmune encephalomyelitis (EAE). Moreover, we demonstrate that enhanced CD74 cell surface expression on monocytes in mice with EAE and subjects with multiple sclerosis (MS) can be down-regulated by humanized RTLs, resulting in reduced MIF binding to the cells. Thus, binding of partial MHC complexes to CD74 blocks both the accessibility and availability of CD74 for MIF binding and downstream inflammatory activity.
TL;DR: Functional promoter polymorphisms in the MIF gene influence plasma MIF levels in AOSd and may contribute to disease susceptibility or clinical presentation of AOSD.
Abstract: Adult-onset still's disease (AOSD) is a rare systemic inflammatory disorder in which abnormalities in inflammatory cytokines production appear to play a pathophysiological role. Our previous work has reported increased expression of macrophage migration inhibitory factor (MIF) and revealed its correlation with disease severity and activity in AOSD. A -173 G/C single nucleotide polymorphism (SNP) (rs755622) and a -794 CATT5-8 repeat (rs5844572) in the MIF promoter have been reported. In this study, we sought to explore the relationship between functional MIF promoter polymorphisms and MIF expression in AOSD. 100 patients and 200 controls were recruited in the study. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was utilized to analyze the -173 G/C SNP (rs755622) and PCR-based size discrimination assay was applied to detect the -794 CATT5-8 repeat (rs5844572) in the MIF promoter. Plasma MIF levels were measured by ELISA. MIF mRNA levels were quantified by real-time reverse transcription (RT)-PCR. Bisulfate genomic sequencing was employed to evaluate DNA methylation status within the MIF promoter. We identified that the frequencies of MIF -794 CATT5 (P = 0.001) allele and the expression of MIF (P <0.001) were increased in patients compared to healthy controls. Plasma levels of MIF in patients with CC genotype were higher than those of patients with GC or GG genotypes (P = 0.05). In patients with established AOSD, a higher frequency of -794 CATT7 containing MIF genotypes was observed in those with liver dysfunction (P = 0.009). Haplotype analysis revealed a higher representation of the MIF haplotype defined by -173*C/-794 CATT5 (C5) in AOSD patients (P = 0.001). Functional promoter polymorphisms in the MIF gene influence plasma MIF levels in AOSD and may contribute to disease susceptibility or clinical presentation of AOSD.
TL;DR: In this paper, the authors investigated the effect of berberine on palmitate-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs).
Abstract: Endothelial dysfunction is a critical factor during the initiation of cardiovascular complications in diabetes. Berberine can ameliorate endothelial dysfunction induced by diabetes. However, the underlying mechanisms remain unclear. The aim of this study was to investigate the protective effect and mechanism of berberine on palmitate-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs). The cell viability of HUVECs was determined by MTT assays. Nitric oxide (NO) level and production of reactive oxygen species (ROS) were determined in supernatants or in the cultured HUVECs. The mRNA level of endothelial nitric oxide synthase (eNOS) was measured by RT-PCR, and the protein levels of eNOS, p-eNOS, Akt, p-Akt, AMPK, p-AMPK, and NADPH oxidase (NOX4) were analyzed. The results demonstrated that berberine significantly elevated NO levels and reduced the production of ROS. The expressions of eNOS were significantly increased, while NOX4 protein expression was decreased in berberine-treated HUVECs. Moreover, berberine upregulated the protein expression of AMPK and p-AMPK in palmitate-treated HUVECs, but had no effect on the levels of Akt. Therefore, berberine ameliorates palmitate-induced endothelial dysfunction by upregulating eNOS expression and downregulating expression of NOX4. This regulatory effect of berberine may be related to the activation of AMPK.
TL;DR: Findings implicate an important role for MIF in radiation-induced changes in lung-cell antioxidant concentrations via Nrf2, and suggest that MIF may contribute to age-related susceptibility to thoracic radiation.
Abstract: Microvascular injury and increased vascular leakage are prominent features of radiation-induced lung injury (RILI), and often follow cancer-associated thoracic irradiation. Our previous studies demonstrated that polymorphisms in the gene (MIF) encoding macrophage migratory inhibition factor (MIF), a multifunctional pleiotropic cytokine, confer susceptibility to acute inflammatory lung injury and increased vascular permeability, particularly in senescent mice. In this study, we exposed wild-type and genetically engineered mif(-/-) mice to 20 Gy single-fraction thoracic radiation to investigate the age-related role of MIF in murine RILI (mice were aged 8 wk, 8 mo, or 16 mo). Relative to 8-week-old mice, decreased MIF was observed in bronchoalveolar lavage fluid and lung tissue of 8- to 16-month-old wild-type mice. In addition, radiated 8- to 16-month-old mif(-/-) mice exhibited significantly decreased bronchoalveolar lavage fluid total antioxidant concentrations with progressive age-related decreases in the nuclear expression of NF-E2-related factor-2 (Nrf2), a transcription factor involved in antioxidant gene up-regulation in response to reactive oxygen species. This was accompanied by decreases in both protein concentrations (NQO1, GCLC, and heme oxygenase-1) and mRNA concentrations (Gpx1, Prdx1, and Txn1) of Nrf2-influenced antioxidant gene targets. In addition, MIF-silenced (short, interfering RNA) human lung endothelial cells failed to express Nrf2 after oxidative (H2O2) challenge, an effect reversed by recombinant MIF administration. However, treatment with an antioxidant (glutathione reduced ester), but not an Nrf2 substrate (N-acetyl cysteine), protected aged mif(-/-) mice from RILI. These findings implicate an important role for MIF in radiation-induced changes in lung-cell antioxidant concentrations via Nrf2, and suggest that MIF may contribute to age-related susceptibility to thoracic radiation.
TL;DR: It is suggested that both MIF and CD74 play a critical role in mediating alphaviral disease, and blocking these factors with novel therapeutic agents could substantially ameliorate the pathologic manifestations.
Abstract: Objective
Arthrogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus (CHIKV) circulate worldwide. This virus class causes debilitating illnesses that are characterized by arthritis, arthralgia, and myalgia. In previous studies, we identified macrophage migration inhibitory factor (MIF) as a critical inflammatory factor in the pathogenesis of alphaviral diseases. The present study was undertaken to characterize the role of CD74, a cell surface receptor of MIF, in both RRV- and CHIKV-induced alphavirus arthritides.
Methods
Mouse models of RRV and CHIKV infection were used to investigate the immunopathogenesis of arthritic alphavirus infection. The role of CD74 was assessed using histologic analysis, real-time polymerase chain reaction, flow cytometry, and plaque assay.
Results
In comparison to wild-type mice, CD74−/− mice developed only mild clinical features and had low levels of tissue damage. Leukocyte infiltration, characterized predominantly by inflammatory monocytes and natural killer cells, was substantially reduced in the infected tissue of CD74−/− mice, but production of proinflammatory cytokines and chemokines was not decreased. CD74 deficiency was associated with increased monocyte apoptosis, but had no effect on monocyte migratory capacity. Consistent with these findings, alphaviral infection resulted in a dose-dependent up-regulation of CD74 expression in human peripheral blood mononuclear cells, and serum MIF levels were significantly elevated in patients with RRV or CHIKV infection.
Conclusion
CD74 appears to regulate immune responses to alphaviral infection through its effects on cellular recruitment and survival. These findings suggest that both MIF and CD74 play a critical role in mediating alphaviral disease, and blocking these factors with novel therapeutic agents could substantially ameliorate the pathologic manifestations.
TL;DR: It is demonstrated that, as a result of CD74 overexpression, the phosphorylation pattern of the C-terminal part of Scribble undergoes specific changes, which is likely to effectively enhance the motility and invasiveness of the cancer cells.
TL;DR: NMR and size-exclusion chromatography with light scattering reveal that N110C can form a higher-order oligomer in equilibrium with a single locked trimer and the X-ray structure confirms a local conformational change that disrupts the subunit interface and results in global changes responsible for the oligomeric form.
Abstract: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine. In addition to its known receptor-mediated biological activities, MIF possesses a catalytic site of unknown function between subunits of a homotrimer. Each subunit contributes three β-strands to adjacent subunits to form a core seven-stranded β-sheet for each monomer. MIF monomers, dimers, or trimers have been reported, but the active form that binds and activates the MIF receptor (CD74) is still a matter of debate. A cysteine mutant (N110C) that covalently locks MIF into a trimer by forming a disulfide with Cys-80 of an adjacent subunit is used to study this issue. Partial catalytic activity and receptor binding to CD74 are retained by N110C (locked trimer), but there is no cellular signaling. Wild-type MIF-induced cellular signaling, in vivo lung neutrophil accumulation, and alveolar permeability are inhibited with a fivefold excess of N110C. NMR and size-exclusion chromatography with light scattering reveal that N110C can form a higher-order oligomer in equilibrium with a single locked trimer. The X-ray structure confirms a local conformational change that disrupts the subunit interface and results in global changes responsible for the oligomeric form. The structure also confirms these changes are consistent for the partial catalytic and receptor binding activities. The absence of any potential monomer and the retention of partial catalytic and receptor binding activities despite changes in conformation (and dynamics) in the mutant support an endogenous MIF trimer that binds and activates CD74 at nanomolar concentrations. This conclusion has implications for therapeutic development.
TL;DR: Loss of MIF exacerbated injury in the female brain after experimental stroke, which was independent of changes in pro-inflammatory cytokine levels.
TL;DR: Evidence is provided that the LupusQoL-China is valid as a disease-specific HRQo lupus erythematosus assessment tool for Chinese patients with SLE.
Abstract: Objectives
To adapt and assess the validity and reliability of LupusQoL for use in Chinese patients with systemic lupus erythematosus (SLE).
TL;DR: Data point to the careful regulatory balance exerted by MIF in the developing lung and response to hyperoxia and support the potential therapeutic value of small molecule MIF modulation in BPD.
Abstract: The role and mechanism of action of MIF in bronchopulmonary dysplasia (BPD) are not known. We hypothesized that increased MIF signaling would ameliorate the pulmonary phenotype of BPD in the mouse lung. We studied newborn wild type (WT), MIF knockout (MIFKO), and lung MIF transgenic (MIFTG) mice in room air and a BPD model, and examined the effects of administering a small molecule MIF agonist and antagonist. Lung morphometry was performed and mRNA and protein expression of vascular mediators were analyzed. The pulmonary phenotype of MIFKO and MIFTG mice lungs in room air (RA) and BPD model were comparable to the WT-BPD mice at postnatal (PN) day 14. Vascular endothelial growth factor (VEGF)-A, -R1 and Angiopoietin (Ang)1 mRNA were decreased, and Ang2 increased in the WT-BPD, MIFKO-RA, MIFKO-BPD, MIFTG-RA and MIFTG-BPD mice lungs, compared to appropriate controls. The protein expression of Ang1 in the MIFKO-RA was similar to WT-RA, but decreased in MIFTG-RA, and decreased in all the BPD groups. Ang2 was increased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. Tie2 was increased in WT-BPD compared to WT-RA, but decreased in MIFKO- and MIFTG- RA and BPD groups. VEGFR1 was uniformly decreased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. VEGF-A had a similar expression across all RA and BPD groups. There was partial recovery of the pulmonary phenotype in the WT-BPD model treated with the MIF agonist, and in the MIFTG mice treated with the MIF antagonist. These data point to the careful regulatory balance exerted by MIF in the developing lung and response to hyperoxia and support the potential therapeutic value of small molecule MIF modulation in BPD.
TL;DR: Data point to the potential roles of Angiopoietins 1, 2 and their receptor Tie2 in the MIF-regulated response in room air and upon hyperoxia exposure in the neonatal lung.
Abstract: Background
The role and mechanism of action of MIF in hyperoxia-induced acute lung injury (HALI) in the newborn lung are not known. We hypothesized that MIF is a critical regulatory molecule in HALI in the developing lung.
TL;DR: The results demonstrated that ISL treatment markedly ameliorated cardiomyocytes contractile dysfunction caused by hypoxia and demonstrated the cardioprotection against ischemic injury that may attribute to the activation of AMPK and ERK signaling pathways and balance of cellular redox status.
Abstract: Isoliquiritigenin (ISL), a simple chalcone-type flavonoid, is derived from licorice compounds and is mainly present in foods, beverages, and tobacco. Reactive oxygen species (ROS) is a critical factor involved in modulating cardiac stress response signaling during ischemia and reperfusion. We hypothesize that ISL as a natural antioxidant may protect heart against ischemic injury via modulating cellular redox status and regulating cardioprotective signaling pathways. The fluorescent probe H2DCFDA was used to measure the level of intracellular ROS. The glucose uptake was determined by 2-deoxy-D-glucose-(3)H accumulation. The IonOptix System measured the contractile function of isolated cardiomyocytes. The results demonstrated that ISL treatment markedly ameliorated cardiomyocytes contractile dysfunction caused by hypoxia. ISL significantly stimulated cardioprotective signaling, AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) signaling pathways. The ROS fluorescent probe H2DCFDA determination indicated that ISL significantly reduced cardiac ROS level during hypoxia/reoxygenation. Moreover, ISL reduced the mitochondrial potential (Δψ) of isolated mouse cardiomyocytes. Taken together, ISL as a natural antioxidant demonstrated the cardioprotection against ischemic injury that may attribute to the activation of AMPK and ERK signaling pathways and balance of cellular redox status.
01 Jan 2013
TL;DR: In this paper, the authors show that when CD74 is overexpressed in human cancer and non-cancerous epithelial cells, it interacts and interferes with the function of Scribble, a product of a well-known tumor suppressor gene.
Abstract: The γ subunit of the major histocompatibility complex (MHC) class II complex, CD74, is overexpressed in a significant proportion of metastatic breast tumors, but the mechanistic foundation and biologic significance of this phenomenon are not fully understood. Here, we show that when CD74 is overexpressed in human cancer and noncancerous epithelial cells, it interacts and interferes with the function of Scribble, a product of a well-known tumor suppressor gene. Furthermore, using epithelial cell lines expressing CD74 under the control of tetracycline-inducible promoter and quantitative high-resolution mass spectrometry, we demonstrate that, as a result of CD74 overexpression, the phosphorylation pattern of the C-terminal part of Scribble undergoes specific changes. This is accompanied with a translocation of the protein from the sites of cell-to-cell contacts at the plasma membrane to the cytoplasm, which is likely to effectively enhance the motility and invasiveness of the cancer cells.
TL;DR: JIA is predominantly a polyarticular rheumatoid factor negative disease in Zambia and there is need to elucidate the genetics and environmental factors of JIA in this region.
Abstract: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders with different disease manifestations among various populations. There are few reports of JIA among indigenous Africans especially sub-Saharan Africa. We present herein the clinical patterns of JIA encountered at a tertiary hospital in Lusaka, Zambia. Hospital records of patients with a diagnosis of chronic arthritis with onset at the age of 16 years or less presenting to University Teaching Hospital, Lusaka, Zambia for the periods 1994–98 and 2006–2010 were retrospectively reviewed and reclassified as Juvenile Idiopathic Arthritis (JIA) based on the International League of Associations for Rheumatology (ILA R) JIA diagnostic criteria. In total, 126 patients with chronic arthritis of onset at age 16 years or less were evaluated over these periods at the hospital. Of these, 85 could further be analyzed by ILAR JIA criteria but 7 (8.24%) were HIV seropositive and were assessed separately. The average age at disease onset among the 78 JIA patients was 8.70 years (range: 1–15 years) with average age at first visit to hospital being 11.3 years (range: 2 to 25 years) and with a female to male ratio of 1.2:1. Polyarticular rheumatoid factor negative JIA, at 34.62%, was the most frequent type of chronic arthritis encountered. Oligoarthritis was found in 32.05% while 11.54% and 14.10% were polyarticular rheumatoid factor positive and systemic JIA, respectively. Enthesitis-related arthritis was found in 6.41% and only 1.28% were determined to have psoriatic arthritis among this population. JIA is predominantly a polyarticular rheumatoid factor negative disease in Zambia. Late presentation is an issue with major implications for educational input and resource acquisition. There is need to elucidate the genetics and environmental factors of JIA in this region.
TL;DR: The role of MIF increase during cardiac surgery in response to oxidative stress is highlighted and it is hypothesized that intraoperative MIF secretion is due to I/R and enhances the antioxidant capacity in patients during heart surgery.
Abstract: Cardiac surgery is associated with release of the pleiotropic cytokine macrophage migration inhibitory factor (MIF). The trigger for MIF release has not yet been elucidated. Owing to its intrinsic antioxidative activity, MIF might reduce oxidative stress and protect from myocardial ischemia and reperfusion (I/R) injury. In the present study, patients scheduled for elective cardiac surgery (n=46) were randomized to undergo coronary artery bypass grafting either conventionally with cardiopulmonary bypass and cardioplegic arrest-induced I/R (cCABG) or in an off-pump procedure (OPCAB) with minimized I/R. We report that only patients who underwent cCABG exhibited a postoperative increase of MIF (p=0.024), while both groups showed an increase in interleukin-6. MIF release appears to be primarily mediated by I/R and to a lesser extent by inflammation. Endogenous peroxidase activity (p=0.021) and serum levels of thioredoxin (p=0.003) were significantly higher in patients who underwent cCABG after surgery...
TL;DR: Results indicate that MIF plays a critical role in inflammation and joint destruction in K/BxN serum-induced arthritis and that the systemic expression of MIF by a subpopulation of macrophages is necessary and sufficient for the full development of arthritis.
Abstract: Rheumatoid arthritis (RA) is characterized by the interaction of multiple mediators, among the most important of which are cytokines. In recent years, extensive studies demonstrate a pivotal role for one cytokine, macrophage migration inhibitory factor (MIF), in fundamental events in innate and adaptive immunity. MIF has now been demonstrated to be involved in the pathogenesis of many diseases, but in the case of RA the evidence for a role of MIF is very strong. MIF is abundantly expressed in the sera of RA patients and in RA synovial tissue correlating with disease activity. MIF-deficient mice were used to induce arthritis by serum transfer from K/BxN mice. K/BxN serum transfer arthritis was markedly attenuated in MIF(-) mice, with reduction in clinical index and histological severity as well as decrease in synovial cytokines. Macrophage transfers were done to investigate the specific role of macrophage-derived MIF. We show that adoptive transfer of wild-type macrophages into MIF(-) mice restores the sensitivity of MIF(-) mice to arthritis development, and this affect was associated with a restoration in serum IL-1β and IL-6 production. These results indicate that MIF plays a critical role in inflammation and joint destruction in K/BxN serum-induced arthritis and that the systemic expression of MIF by a subpopulation of macrophages is necessary and sufficient for the full development of arthritis.
TL;DR: In this article, the first characterization of Neospora caninum macrophage migration inhibitory factor (NcMIF) was performed in Escherichia coli.
TL;DR: The results suggest that CD45+/Col1+ cells may be directly involved, in part through CCL2/CCR2 signaling, in the fibrotic process under diabetic conditions.
Abstract: Background
The migration and activation of circulating profibrotic cells including fibrocytes by the action of the chemokine/chemokine receptor system has been implicated in pathological fibrogenesis. In the present study, the involvement of collagen 1 (Col1)-producing cells, CD45-positive/collagen-1-positive (CD45+/Col1+) cells originally named as fibrocytes via CC chemokine receptor 2 (CCR2), a cognate receptor of CCL2/monocyte chemoattractant protein, was examined in diabetic conditions.
Patent•
26 Nov 2013
TL;DR: Methods and compositions for using the MHC class II invariant chain polypeptide, Ii (also known as CD74), as a receptor for macrophage migration inhibitory factor (MIF), are disclosed in this paper.
Abstract: Methods and compositions for using the MHC class II invariant chain polypeptide, Ii (also known as CD74), as a receptor for macrophage migration inhibitory factor (MIF), are disclosed. These include methods and compositions for using this receptor, as well as agonists and antagonists of MIF which bind to this receptor, or which otherwise modulate the interaction of MIF with CD74 or the consequences of such interaction, in treatment of conditions characterized by locally or systemically altered MIF levels, particularly inflammatory conditions and cancer.