2024
A small-molecule allele-selective transcriptional inhibitor of the MIF immune susceptibility locus
Li J, Leng L, Pantouris G, Manjula R, Piecychna M, Abriola L, Hu B, Lolis E, Armstrong M, Donnelly S, Bucala R. A small-molecule allele-selective transcriptional inhibitor of the MIF immune susceptibility locus. Journal Of Biological Chemistry 2024, 300: 107443. PMID: 38838773, PMCID: PMC11259703, DOI: 10.1016/j.jbc.2024.107443.Peer-Reviewed Original ResearchPromoter microsatellitesGene expressionMicrosatellite repeat numberMacrophage migration inhibitory factorLength-dependent mannerRNA expression analysisSusceptibility lociFunctional variantsSmall molecule inhibitorsExpression analysisPharmacogenomic developmentRepeat numberMicrosatelliteFunctional interactionsTranscription inhibitorInflammatory gene expressionMIF mRNA expressionCytokine macrophage migration inhibitory factorTranscriptionGenesProtein expressionMigration inhibitory factorExpressionInhibitory factorExpressing macrophagesIguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose
Bloom J, Pantouris G, He M, Aljabari B, Mishra L, Manjula R, Parkins A, Lolis E, Al-Abed Y. Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose. Molecular Medicine 2024, 30: 43. PMID: 38539088, PMCID: PMC10976746, DOI: 10.1186/s10020-024-00803-0.Peer-Reviewed Original ResearchConceptsMode of inhibitionAllosteric inhibitorsActive site pocketMigration inhibitory factorSite pocketInhibitory factorProtein crystallographyTautomerase active siteOxidative stressT-614Murine modelDrug modePleiotropic cytokineNon-competitive type of inhibitionAPAP overdoseActive siteMacrophage migration inhibitory factorInhibition constantType of inhibitionInhibitor of macrophage migration inhibitory factorKinetic analysisBackgroundMacrophage migration inhibitory factorAcetaminophen overdoseIn vivo experimentsMultiple small molecule inhibitors
2023
Plant MDL proteins synergize with the cytokine MIF at CXCR2 and CXCR4 receptors in human cells
Spiller L, Manjula R, Leissing F, Basquin J, Bourilhon P, Sinitski D, Brandhofer M, Levecque S, Gerra S, Sabelleck B, Zhang L, Feederle R, Flatley A, Hoffmann A, Panstruga R, Bernhagen J, Lolis E. Plant MDL proteins synergize with the cytokine MIF at CXCR2 and CXCR4 receptors in human cells. Science Signaling 2023, 16: eadg2621. PMID: 37988455, DOI: 10.1126/scisignal.adg2621.Peer-Reviewed Original ResearchConceptsMammalian macrophage migration inhibitory factorHetero-oligomeric complexesHigh structural similarityMultifunctional inflammatory cytokineHuman lung epithelial cellsYeast reporter systemReporter systemLung epithelial cellsPlant leavesFunctional similarityCellular responsesHuman cellsPharmacological inhibitorsDopachrome tautomeraseFunctional implicationsX-ray crystallographyMacrophage migration inhibitory factorStructural similarityEpithelial cellsMigration inhibitory factorCXCR4 receptorProteinTautomerase activityCellsMIF receptor
2022
A Cysteine Variant at an Allosteric Site Alters MIF Dynamics and Biological Function in Homo- and Heterotrimeric Assemblies
Skeens E, Pantouris G, Shah D, Manjula R, Ombrello MJ, Maluf NK, Bhandari V, Lisi GP, Lolis EJ. A Cysteine Variant at an Allosteric Site Alters MIF Dynamics and Biological Function in Homo- and Heterotrimeric Assemblies. Frontiers In Molecular Biosciences 2022, 9: 783669. PMID: 35252348, PMCID: PMC8893199, DOI: 10.3389/fmolb.2022.783669.Peer-Reviewed Original ResearchAllosteric siteNon-overlapping functionsEnzymatic activityHeterotrimeric assemblyBiological functionsWild typeCatalytic baseCysteine variantsFunctional interactionHuman macrophage migration inhibitory factorSolvent channelsMacrophage migration inhibitory factorEnzymatic cavityCrystallographic structureNMR dynamicsMixed wild typeVariantsY99CInhibitory factorMammalsNucleaseSubunitsCytosolDifferent extentsFish
2019
Selective Recruitment of Lethal Pro-inflammatory Macrophages in Sepsis by MIF but not D-DT (MIF-2)
Tilstam P, Schulte W, Holowka T, Kim B, Piecychna M, Pantouris G, Lolis E, Leng L, Bernhagen J, Bucala R. Selective Recruitment of Lethal Pro-inflammatory Macrophages in Sepsis by MIF but not D-DT (MIF-2). The Journal Of Immunology 2019, 202: 51.9-51.9. DOI: 10.4049/jimmunol.202.supp.51.9.Peer-Reviewed Original ResearchMacrophage migration inhibitory factorSmall peritoneal macrophagesLarge peritoneal macrophagesPolymicrobial sepsisPeritoneal macrophagesMIF receptor CD74MIF promoter polymorphismsMigration inhibitory factorPro-inflammatory macrophagesSelective roleDate interventionsMIF deficiencyAdoptive transferSurvival benefitInfectious insultsMIF antibodyInflammatory cytokinesPeritoneal inflammationReceptor CD74Inflammatory pathwaysLeading causeSepsis lethalityInflammatory responseAbstract SepsisGlobal incidence
2018
Nanosecond Dynamics Regulate the MIF‐Induced Activity of CD74
Pantouris G, Ho J, Shah D, Syed M, Leng L, Bhandari V, Bucala R, Batista V, Loria J, Lolis E. Nanosecond Dynamics Regulate the MIF‐Induced Activity of CD74. Angewandte Chemie 2018, 130: 7234-7237. DOI: 10.1002/ange.201803191.Peer-Reviewed Original ResearchMacrophage migration inhibitory factorMigration inhibitory factorNanosecond Dynamics Regulate the MIF‐Induced Activity of CD74
Pantouris G, Ho J, Shah D, Syed MA, Leng L, Bhandari V, Bucala R, Batista VS, Loria JP, Lolis E. Nanosecond Dynamics Regulate the MIF‐Induced Activity of CD74. Angewandte Chemie International Edition 2018, 57: 7116-7119. PMID: 29669180, PMCID: PMC6282165, DOI: 10.1002/anie.201803191.Peer-Reviewed Original Research
2016
Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions*
Rajasekaran D, Gröning S, Schmitz C, Zierow S, Drucker N, Bakou M, Kohl K, Mertens A, Lue H, Weber C, Xiao A, Luker G, Kapurniotu A, Lolis E, Bernhagen J. Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions*. Journal Of Biological Chemistry 2016, 291: 15881-15895. PMID: 27226569, PMCID: PMC4957068, DOI: 10.1074/jbc.m116.717751.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorChemokine receptorsCXCR4 receptorRole of MIFMIF's biological activityMigration inhibitory factorChemokine receptor interactionsFunctional CXCR4 receptorsClassical chemokine receptorsChemokine-like activityPartial allosteric agonistRegions of CXCR4Inflammatory cytokinesReceptor CD74Leukocyte recruitmentAllosteric agonistInhibitory factorCXCR4Non-cognate interactionsReceptorsPharmacological reagentsReceptor interactionArray analysisGenetic strainsCritical biological responses
2010
AV411 (Ibudilast) and AV1013 are non-competitive inhibitors of macrophage migration inhibitory factor: a novel induced-fit allosteric inhibition mechanism (133.11)
Cho Y, Crichlow G, Vermeire J, Leng L, Du X, Hodsdon M, Bucala R, Cappello M, Gross M, Gaeta F, Johnson K, Lolis E. AV411 (Ibudilast) and AV1013 are non-competitive inhibitors of macrophage migration inhibitory factor: a novel induced-fit allosteric inhibition mechanism (133.11). The Journal Of Immunology 2010, 184: 133.11-133.11. DOI: 10.4049/jimmunol.184.supp.133.11.Peer-Reviewed Original ResearchMacrophage migration inhibitory factorMigration inhibitory factorInhibitory factorPro-inflammatory proteinsAnti-inflammatory activityAnti-inflammatory drugsNon-selective inhibitorPDE inhibitor rolipramNeuropathic painOpioid withdrawalBronchial asthmaOcular indicationsGlial cellsNon-competitive inhibitorPossible therapeuticsInhibitor rolipramChemotactic functionAV411Tautomerase activityInhibitorsAllosteric binding siteIsobutylmethylxanthineTreatmentAsthmaPain
2001
Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery
Lolis E. Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery. Current Opinion In Pharmacology 2001, 1: 662-668. PMID: 11757824, DOI: 10.1016/s1471-4892(01)00112-6.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAmino Acid SequenceAnimalsCOP9 Signalosome ComplexDNA-Binding ProteinsDrug DesignGenes, p53GlucocorticoidsHumansInflammationInflammation MediatorsIntracellular Signaling Peptides and ProteinsMacrophage Migration-Inhibitory FactorsMembrane ProteinsMolecular Sequence DataNeoplasmsNeovascularization, PathologicPeptide HydrolasesPhosphoproteinsStructure-Activity RelationshipTranscription FactorsConceptsMacrophage migration inhibitory factorMigration inhibitory factorContribution of MIFInhibitory factorElevated MIF levelsMIF's biological activityActivity of CD4Natural killer cellsInflammatory neurological diseasesInflammatory lung diseasesMIF levelsUlcerative colitisKiller cellsRheumatoid arthritisLung diseaseInflammatory diseasesT cellsHuman studiesNeurological diseasesTherapeutic interventionsDiseaseEndothelial cellsNumber of diseasesIntracellular regulatory proteinsCancerDevelopment of chronic colitis is dependent on the cytokine MIF
de Jong Y, Abadia-Molina A, Satoskar A, Clarke K, Rietdijk S, Faubion W, Mizoguchi E, Metz C, Sahli M, ten Hove T, Keates A, Lubetsky J, Farrell R, Michetti P, van Deventer S, Lolis E, David J, Bhan A, Terhorst C. Development of chronic colitis is dependent on the cytokine MIF. Nature Immunology 2001, 2: 1061-1066. PMID: 11668338, DOI: 10.1038/ni720.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAutoimmune DiseasesBone Marrow TransplantationChronic DiseaseColitisCrohn DiseaseDNA-Binding ProteinsFemaleHumansImmunization, PassiveLipopolysaccharidesMacrophage ActivationMacrophage Migration-Inhibitory FactorsMaleMiceMice, KnockoutModels, AnimalNuclear ProteinsRadiation ChimeraWeight LossConceptsMacrophage migration inhibitory factorCytokine macrophage migration inhibitory factorMIF-deficient miceCrohn's diseaseRole of MIFImmune systemPlasma MIF concentrationMucosal immune systemInnate immune cellsInnate immune systemChronic colitisMIF concentrationsExperimental colitisMIF productionMurine colitisImmune cellsColitisIntestinal bacteriaInhibitory factorDiseaseNew targetsMiceLipopolysaccharideCell typesPatients
1999
Pro-1 of Macrophage Migration Inhibitory Factor Functions as a Catalytic Base in the Phenylpyruvate Tautomerase Activity † , ‡
Lubetsky J, Swope M, Dealwis C, Blake P, Lolis E. Pro-1 of Macrophage Migration Inhibitory Factor Functions as a Catalytic Base in the Phenylpyruvate Tautomerase Activity † , ‡. Biochemistry 1999, 38: 7346-7354. PMID: 10353846, DOI: 10.1021/bi990306m.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionAnimalsBinding SitesCatalysisCrystallography, X-RayEnzyme ActivationGlycineHumansHydrogen-Ion ConcentrationIntramolecular OxidoreductasesMacromolecular SubstancesMacrophage Migration-Inhibitory FactorsMethionineMutagenesis, Site-DirectedNuclear Magnetic Resonance, BiomolecularPhenylpyruvic AcidsProlineRecombinant ProteinsConceptsMacrophage migration inhibitory factorMacrophage migration inhibitory factor (MIF) functionsAnti-inflammatory effectsMigration inhibitory factorImportant immunoregulatory moleculeTautomerase activityImmunoregulatory moleculesPhenylpyruvate tautomerase activityInhibitory factorP-hydroxyphenylpyruvateGlucocorticoidsPro-1CytokinesActivity
1998
Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor
Swope M, Sun H, Blake P, Lolis E. Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor. The EMBO Journal 1998, 17: 3534-3541. PMID: 9649424, PMCID: PMC1170690, DOI: 10.1093/emboj/17.13.3534.Peer-Reviewed Original ResearchConceptsN-terminal prolineN-terminal regionStructure-based inhibitorsMultiple sequence alignmentThree-dimensional structureInvariant residuesEntire polypeptideMicrobial enzymesCatalytic basePro-1Sequence alignmentMIF homologuesCytokine activityHuman macrophage migration inhibitory factorCatalytic siteProlineInhibitory factorHomologuesUnderlying biological activityP-hydroxyphenylpyruvateProteinMacrophage migration inhibitory factorActive siteBiological activity