2025
IL-4 mediated TAP2 downregulation is a dominant and reversible mechanism of immune evasion and immunotherapy resistance in non-small cell lung cancer
Ranjan K, Rajendran B, Deen I, Costantini A, de Rodas M, Desai S, Scallo F, Gianino N, Ferrone S, Schalper K. IL-4 mediated TAP2 downregulation is a dominant and reversible mechanism of immune evasion and immunotherapy resistance in non-small cell lung cancer. Molecular Cancer 2025, 24: 80. PMID: 40091029, PMCID: PMC11912681, DOI: 10.1186/s12943-025-02276-z.Peer-Reviewed Original ResearchThis study investigates IL-4's role in TAP2 downregulation as a reversible mechanism of immune evasion and resistance to immunotherapy in non-small cell lung cancer, highlighting potential therapeutic strategies to restore TAP2 expression and enhance treatment efficacy.
2024
Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages
Liebold I, Al Jawazneh A, Casar C, Lanzloth C, Leyk S, Hamley M, Wong M, Kylies D, Gräfe S, Edenhofer I, Aranda-Pardos I, Kriwet M, Haas H, Krause J, Hadjilaou A, Schromm A, Richardt U, Eggert P, Tappe D, Weidemann S, Ghosh S, Krebs C, A-Gonzalez N, Worthmann A, Lohse A, Huber S, Rothlin C, Puelles V, Jacobs T, Gagliani N, Bosurgi L. Apoptotic cell identity induces distinct functional responses to IL-4 in efferocytic macrophages. Science 2024, 384: eabo7027. PMID: 38574142, DOI: 10.1126/science.abo7027.Peer-Reviewed Original ResearchConceptsApoptotic neutrophilsApoptotic cellsIL-4-induced gene expressionUptake of apoptotic neutrophilsApoptotic cell clearanceCell lineage identityResponse to IL-4Cell identityEfferocytic macrophagesPhagocytic receptorsGene expressionLineage identityCell clearanceApoptotic hepatocytesHeterogeneous cellsCellsMouse modelT cellsParasite-induced pathologyIL-4HepatocytesMacrophagesInterleukin-4EngulfmentPhenotype
2023
An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis
LaMarche N, Hegde S, Park M, Maier B, Troncoso L, Le Berichel J, Hamon P, Belabed M, Mattiuz R, Hennequin C, Chin T, Reid A, Reyes-Torres I, Nemeth E, Zhang R, Olson O, Doroshow D, Rohs N, Gomez J, Veluswamy R, Hall N, Venturini N, Ginhoux F, Liu Z, Buckup M, Figueiredo I, Roudko V, Miyake K, Karasuyama H, Gonzalez-Kozlova E, Gnjatic S, Passegué E, Kim-Schulze S, Brown B, Hirsch F, Kim B, Marron T, Merad M. An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature 2023, 625: 166-174. PMID: 38057662, PMCID: PMC11189607, DOI: 10.1038/s41586-023-06797-9.Peer-Reviewed Original ResearchConceptsInterleukin-4IL-4RαMyeloid cellsCheckpoint blockadeTumor burdenPD-1/PD-L1 checkpoint blockadePD-1/PD-L1 blockadeBone marrowTumor-infiltrating CD8 T cellsType 2 cytokines interleukin-4PD-L1 checkpoint blockadeCell lung cancer lesionsNon-small cell lung cancer lesionsDepletion of basophilsPD-L1 blockadePrimary disease siteCD8 T cellsImmune checkpoint blockadeLung cancer lesionsNovel combination therapiesCytokine interleukin-4Bone marrow basophilsConditional knockout miceRefractory NSCLCEarly myeloid progenitorsEnhanced alloresponse to platelet transfusion due to immune dysregulation following ablative chemotherapy in mice
Jackman R, Darst O, Gaillard B, Tran J, Tomayko M, Muench M. Enhanced alloresponse to platelet transfusion due to immune dysregulation following ablative chemotherapy in mice. Frontiers In Immunology 2023, 14: 1281123. PMID: 38090570, PMCID: PMC10711281, DOI: 10.3389/fimmu.2023.1281123.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood PlateletsBlood TransfusionHumansInterleukin-4IsoantibodiesMicePlatelet TransfusionConceptsAblative chemotherapyAlloantibody responsesPlatelet transfusionsB cellsPotent immunological effectsT cell responsesImpact of chemotherapyTransitional B cellsAllogeneic platelet transfusionsRisk of alloimmunizationNon-specific activationSubsequent transfusionsAllogeneic plateletsLymphocyte depletionBlood transfusionImmune dysregulationPlatelet recipientsSerum levelsPatient populationImmunological effectsImmunological environmentTransfusionRejection of transplantsChemotherapyHealthy peopleBRD4‐PRC2 represses transcription of T‐helper 2‐specific negative regulators during T‐cell differentiation
Zhao L, Wang Y, Jaganathan A, Sun Y, Ma N, Li N, Han X, Sun X, Yi H, Fu S, Han F, Li X, Xiao K, Walsh M, Zeng L, Zhou M, Cheung K. BRD4‐PRC2 represses transcription of T‐helper 2‐specific negative regulators during T‐cell differentiation. The EMBO Journal 2023, 42: embj2022111473. PMID: 36719036, PMCID: PMC10015369, DOI: 10.15252/embj.2022111473.Peer-Reviewed Original ResearchConceptsPolycomb repressive complex 2Cell lineage differentiationTranscriptional repressionPolycomb repressive complex 2 complexHistone H3 lysine 27 trimethylationH3 lysine 27 trimethylationTranscriptional de-repressionTarget gene lociCell type-specific mannerGene transcriptional repressionLysine 27 trimethylationLineage differentiationGene repressionTranscription factor GATA3Gene locusTranscriptional activityTranscriptional programsNegative regulatorLineage-specific differentiationTranscriptional downregulationProtein degradationChemical inhibitionTranscript expressionBrd4's roleBRD4
2021
MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis
Zhong C, Min K, Zhao Z, Zhang C, Gao E, Huang Y, Zhang X, Baldini M, Roy R, Yang X, Koch WJ, Bennett AM, Yu J. MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis. Frontiers In Immunology 2021, 12: 790511. PMID: 34992607, PMCID: PMC8724134, DOI: 10.3389/fimmu.2021.790511.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood PressureCardiomegalyCells, CulturedDisease Models, AnimalDual-Specificity PhosphatasesEchocardiographyFibrosisHeartHeart FailureHumansInterleukin-4MacrophagesMaleMAP Kinase Signaling SystemMatrix Metalloproteinase 9MiceMice, KnockoutMyocardiumPhosphorylationPrimary Cell CultureVentricular RemodelingConceptsMitogen-activated protein kinase phosphatase 5Transverse aortic constrictionCardiac fibrosisMMP-9 expressionPressure overloadCardiac hypertrophyPressure overload-induced cardiac fibrosisOverload-induced cardiac fibrosisTAC-induced cardiac hypertrophyExcessive extracellular matrix depositionPro-fibrotic macrophagesCardiac pressure overloadP38 MAPKMatrix metalloproteinase-9Regulation of MMPsProtein kinase phosphatase 5JNK/ERKIL-4 stimulationExtracellular matrix depositionCardiac injuryAortic constrictionMyocardial fibrosisHeart diseaseFibrotic remodelingMetalloproteinase-9
2019
Atopic Dermatitis Is an IL-13–Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis
Tsoi L, Rodriguez E, Degenhardt F, Baurecht H, Wehkamp U, Volks N, Szymczak S, Swindell W, Sarkar M, Raja K, Shao S, Patrick M, Gao Y, Uppala R, Perez White B, Getsios S, Harms P, Maverakis E, Elder J, Franke A, Gudjonsson J, Weidinger S. Atopic Dermatitis Is an IL-13–Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis. Journal Of Investigative Dermatology 2019, 139: 1480-1489. PMID: 30641038, PMCID: PMC6711380, DOI: 10.1016/j.jid.2018.12.018.Peer-Reviewed Original ResearchConceptsTranscriptomic studiesPaired-end readsRNA sequencing samplesPathophysiology of ADPaired-endHigh-resolution viewStudies of ADAD transcriptomeDrug target predictionRNA sequencingLong noncoding RNAsRNA samplesDysregulated genesNoncoding RNAsRNAPsoriasis transcriptomeTranscriptomeCellular featuresGenesMolecular heterogeneityDisease heterogeneityTranslational impactIL-4 expressionAD skinGlobal architecture
2018
Nonredundant Roles of IL-21 and IL-4 in the Phased Initiation of Germinal Center B Cells and Subsequent Self-Renewal Transitions.
Gonzalez DG, Cote CM, Patel JR, Smith CB, Zhang Y, Nickerson KM, Zhang T, Kerfoot SM, Haberman AM. Nonredundant Roles of IL-21 and IL-4 in the Phased Initiation of Germinal Center B Cells and Subsequent Self-Renewal Transitions. The Journal Of Immunology 2018, 201: 3569-3579. PMID: 30446568, PMCID: PMC6289626, DOI: 10.4049/jimmunol.1500497.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisB-LymphocytesCell DifferentiationCell Self RenewalCells, CulturedGerminal CenterInterleukin-4InterleukinsLymphocyte ActivationMiceMice, KnockoutParacrine CommunicationProto-Oncogene Proteins c-bcl-6Receptors, Interleukin-21Signal TransductionSTAT6 Transcription FactorT-Lymphocytes, Helper-InducerConceptsIL-21IL-4B cellsIL-21RCytokine IL-21Costimulatory molecule expressionB cell folliclesIL-21 signalingGC B cell developmentNonredundant roleGerminal center B cellsMurine model systemGC B cellsMolecule expressionPhenotypic maturationB cell developmentCell expressionCytokine signalsB cell transitionCombined absenceSubsequent maturationCell migrationCell development
2017
The vascular endothelial specific IL-4 receptor alpha–ABL1 kinase signaling axis regulates the severity of IgE-mediated anaphylactic reactions
Yamani A, Wu D, Waggoner L, Noah T, Koleske AJ, Finkelman F, Hogan SP. The vascular endothelial specific IL-4 receptor alpha–ABL1 kinase signaling axis regulates the severity of IgE-mediated anaphylactic reactions. Journal Of Allergy And Clinical Immunology 2017, 142: 1159-1172.e5. PMID: 29157947, PMCID: PMC5957775, DOI: 10.1016/j.jaci.2017.08.046.Peer-Reviewed Original ResearchConceptsIgE-mediated anaphylactic reactionsAnaphylactic reactionsFluid extravasationIL-4RαBarrier dysfunctionIL-4Food-induced anaphylactic reactionsIgE-induced anaphylaxisFood-induced anaphylaxisIgE-mediated anaphylaxisIL-4 receptor α chainIgE-mediated reactionsTreatment of miceSevere anaphylactic reactionsSeverity of anaphylaxisABL kinase inhibitor imatinibKinase inhibitor imatinibReceptor α chainVe cell linesVenous vasodilatationOral antigenHypovolemic shockInhibitor imatinibAnaphylaxisVe cellsYeast-expressed recombinant As16 protects mice against Ascaris suum infection through induction of a Th2-skewed immune response
Wei J, Versteeg L, Liu Z, Keegan B, Gazzinelli-Guimarães AC, Fujiwara RT, Briggs N, Jones KM, Strych U, Beaumier CM, Bottazzi ME, Hotez PJ, Zhan B. Yeast-expressed recombinant As16 protects mice against Ascaris suum infection through induction of a Th2-skewed immune response. PLOS Neglected Tropical Diseases 2017, 11: e0005769. PMID: 28708895, PMCID: PMC5529013, DOI: 10.1371/journal.pntd.0005769.Peer-Reviewed Original ResearchConceptsTh2-skewed immune responseTh2-type responseCholera toxin B subunitImmune responseEgg challengeProtective immunitySignificant protectionPredominant Th2-type responseTh2-type immune responseFeasible vaccine candidateTh1-type responseCommon helminth infectionA. suum infectionAscaris suum infectionExact protective mechanismHost immune systemToxin B subunitA. suumRestimulated splenocytesA. suum eggsChallenge infectionIL-4IL-5Trichuris infectionHelminth infectionsStat6 Promotes Intestinal Tumorigenesis in a Mouse Model of Adenomatous Polyposis by Expansion of MDSCs and Inhibition of Cytotoxic CD8 Response
Jayakumar A, Bothwell ALM. Stat6 Promotes Intestinal Tumorigenesis in a Mouse Model of Adenomatous Polyposis by Expansion of MDSCs and Inhibition of Cytotoxic CD8 Response. Neoplasia 2017, 19: 595-605. PMID: 28654863, PMCID: PMC5487300, DOI: 10.1016/j.neo.2017.04.006.Peer-Reviewed Original ResearchMeSH KeywordsAdenomatous Polyposis ColiAnimalsBecaplerminBiomarkersCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell Transformation, NeoplasticCytotoxicity, ImmunologicDisease Models, AnimalDisease ProgressionGene DeletionGene ExpressionInterleukin-4Intestinal MucosaIntestine, SmallMiceMice, KnockoutMyeloid-Derived Suppressor CellsProgrammed Cell Death 1 ReceptorProto-Oncogene Proteins c-sisSTAT6 Transcription FactorConceptsIntestinal tumorigenesisIL-4-induced STAT6Tumor-promoting growth factorsAntitumor T-cell responsesHuman colorectal cancer tissuesMore CD8 cellsPD-1 expressionEpithelial cellsExpansion of MDSCsT cell responsesIL-4 expressionCell proliferationColorectal cancer tissuesPlatelet-derived growth factor-BBIntestinal tumor progressionIntestinal epithelial cellsGrowth factor-BBColon cancer cell linesCD8 responsesPolyp progressionStrong CD8Cancer cell linesCD4 cellsCD8 cellsImmunosuppressive mediatorsMacrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells
Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, Weinstein JS, Licona-Limon P, Schmid ET, Pelorosso F, Gagliani N, Craft JE, Flavell RA, Ghosh S, Rothlin CV. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science 2017, 356: 1072-1076. PMID: 28495875, PMCID: PMC5556699, DOI: 10.1126/science.aai8132.Peer-Reviewed Original ResearchConceptsApoptotic cellsTissue repair programChemotaxis genesTissue-resident macrophagesIL-4IL-13Tissue repairPattern recognition receptorsTissue repair genesCell adhesionRepair genesGenetic ablationCytokine-dependent inductionHelminth infectionsRecognition receptorsInduction of colitisGenesBroad repertoireSoluble cytokinesMacrophage functionCellsInductionHost responseEctopic activityInterleukin-4IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge
Spadaro O, Camell CD, Bosurgi L, Nguyen KY, Youm YH, Rothlin CV, Dixit VD. IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge. Cell Reports 2017, 19: 225-234. PMID: 28402847, PMCID: PMC5513500, DOI: 10.1016/j.celrep.2017.03.046.Peer-Reviewed Original ResearchConceptsMacrophage activationM2-like stateHelminth Nippostrongylus brasiliensisNormal insulin sensitivityAdipose tissue macrophagesHigh-fat dietM2-like macrophage activationTyrosine hydroxylase expressionM2-like macrophagesMacrophage activation phenotypeInsulin resistanceInsulin sensitivityHydroxylase expressionImmunometabolic responsesElevated adipositySpecific cytokinesKnockout miceAdipose tissueMacrophage phenotypeMyeloid cellsNippostrongylus brasiliensisTissue macrophagesPhagocytic activityIGF1 receptorCold challengeChitin and Its Effects on Inflammatory and Immune Responses
Elieh Ali Komi D, Sharma L, Dela Cruz CS. Chitin and Its Effects on Inflammatory and Immune Responses. Clinical Reviews In Allergy & Immunology 2017, 54: 213-223. PMID: 28251581, PMCID: PMC5680136, DOI: 10.1007/s12016-017-8600-0.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsImmune cellsCytokine productionImmune systemAdaptive immune cellsAlternative macrophage activationHost immune systemPathogen-associated molecular patternsPattern recognition receptorsTLR-2Mammalian immune systemImmunological aspectsAllergic responsesIntraperitoneal administrationLeukocyte recruitmentImmune responseAdaptive immunityMacrophage activationImmune recognitionRecognition receptorsTrue chitinasesNKR-P1Molecular patternsPotential targetMammalian chitinasesMammalian receptors
2016
Allergy-specific Phenome-Wide Association Study for Immunogenes in Turkish Children
Karaca S, Civelek E, Karaca M, Sahiner UM, Ozgul RK, Kocabas CN, Polimanti R, Sekerel BE. Allergy-specific Phenome-Wide Association Study for Immunogenes in Turkish Children. Scientific Reports 2016, 6: 33152. PMID: 27624002, PMCID: PMC5021980, DOI: 10.1038/srep33152.Peer-Reviewed Original ResearchConceptsHypertonic saline challenge testTurkish childrenAllergic airway inflammationPhenome-wide association studySkin prick testRole of immunogeneticsCross-sectional studyDifferent immune functionsAllergic bronchitisCD14 rs2569190Airway inflammationAtopic marchPrick testAsthma diagnosisLung functionBlood testsIL4 rs2243250Immune functionChallenge testAssociation studiesADAM33ComorbiditiesChildrenAssociationAsthmaTFH cells progressively differentiate to regulate the germinal center response
Weinstein JS, Herman EI, Lainez B, Licona-Limón P, Esplugues E, Flavell R, Craft J. TFH cells progressively differentiate to regulate the germinal center response. Nature Immunology 2016, 17: 1197-1205. PMID: 27573866, PMCID: PMC5030190, DOI: 10.1038/ni.3554.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibody AffinityB-LymphocytesCD4 AntigensCell CommunicationCell DifferentiationCells, CulturedGene Expression RegulationGerminal CenterHumansInterleukin-4InterleukinsMiceMice, Inbred C57BLMice, Mutant StrainsMutationNippostrongylusPositive Regulatory Domain I-Binding Factor 1Strongylida InfectionsT-Lymphocytes, Helper-InducerTranscription FactorsThe TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity
Chan PY, Carrera Silva EA, De Kouchkovsky D, Joannas LD, Hao L, Hu D, Huntsman S, Eng C, Licona-Limón P, Weinstein JS, Herbert DR, Craft JE, Flavell RA, Repetto S, Correale J, Burchard EG, Torgerson DG, Ghosh S, Rothlin CV. The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity. Science 2016, 352: 99-103. PMID: 27034374, PMCID: PMC4935984, DOI: 10.1126/science.aaf1358.Peer-Reviewed Original ResearchMeSH KeywordsAdaptive ImmunityAnimalsAsthmaBlood ProteinsDendritic CellsDisease Models, AnimalGene Knockout TechniquesHost-Parasite InteractionsHumansImmunity, InnateInterleukin-4MiceMice, Inbred C57BLMice, KnockoutNippostrongylusProtein SPyroglyphidaeReceptor Protein-Tyrosine KinasesStrongylida InfectionsT-LymphocytesConceptsType 2 immunityType 2 responsesType 2 cytokinesHuman dendritic cellsInnate immune cellsDendritic cellsAllergic diseasesImmune cellsT cellsAdaptive immunityInterleukin-4Host responseFunctional neutralizationGenetic ablationReceptor tyrosine kinasesImmunityProtective functionTyro3Tyrosine kinaseNegative regulatorPROS1CellsResponseCytokinesDiseaseIL4 gene polymorphisms in Iranian patients with autoimmune hepatitis
Yousefi A, Mahmoudi E, Bidoki A, Varzaneh F, Noveiry B, Sadr M, Motamed F, Najafi M, Farahmand F, Rezaei N. IL4 gene polymorphisms in Iranian patients with autoimmune hepatitis. Expert Review Of Gastroenterology & Hepatology 2016, 10: 659-663. PMID: 26735262, DOI: 10.1586/17474124.2016.1139449.Peer-Reviewed Original ResearchConceptsAutoimmune hepatitisC alleleAssociation of autoimmune hepatitisMechanisms of autoimmune hepatitisAutoimmune hepatitis patientsAllelic polymorphismInvestigate potential associationsPotential therapeutic interventionsHepatocellular inflammationAuto-antibodiesTT genotypeCC genotypeGene polymorphismsIranian patientsIL4 geneGene variantsIL4RA geneSusceptibility genesIL4Therapeutic interventionsHepatitisPatientsGenetic componentGenesPolymorphism
2015
IL-21 Promotes Pulmonary Fibrosis through the Induction of Profibrotic CD8+ T Cells
Brodeur TY, Robidoux TE, Weinstein JS, Craft J, Swain SL, Marshak-Rothstein A. IL-21 Promotes Pulmonary Fibrosis through the Induction of Profibrotic CD8+ T Cells. The Journal Of Immunology 2015, 195: 5251-5260. PMID: 26519529, PMCID: PMC4655158, DOI: 10.4049/jimmunol.1500777.Peer-Reviewed Original Research
2014
Dynamic signaling by T follicular helper cells during germinal center B cell selection
Shulman Z, Gitlin AD, Weinstein JS, Lainez B, Esplugues E, Flavell RA, Craft JE, Nussenzweig MC. Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science 2014, 345: 1058-1062. PMID: 25170154, PMCID: PMC4519234, DOI: 10.1126/science.1257861.Peer-Reviewed Original ResearchConceptsFollicular helper cellsB cellsGC B cellsHelper cellsGerminal centersAntibody-producing B cellsCytokine interleukin-4B cell selectionGerminal center B cell selectionInterleukin-4Transient elevationMajor histocompatibilitySustained increaseFree calciumClonal expansionCognate peptideIntravital imagingCell migrationCellsIntracellularCell selectionHigh levelsHistocompatibility
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