2024
Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties.
Shin J, Park J, Lim J, Jeong J, Dinesh R, Maher S, Kim J, Park S, Hong J, Wysolmerski J, Choi J, Bothwell A. Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties. ELife 2024, 13 PMID: 39535280, PMCID: PMC11560131, DOI: 10.7554/elife.97279.Peer-Reviewed Original ResearchConceptsCancer cellsDickkopf-2Analysis of transcriptomeGeneration of cancer cellsPositive cancer cellsStem cell niche factorsColon cancer cellsPaneth cell differentiationHepatocyte nuclear factor 4 alphaLysozyme positive cellsChromatin accessibilityHNF4A proteinSingle-cell RNA sequencing analysisCell propertiesPaneth cell markersSequence analysisChromatin immunoprecipitationPromoter regionTranscription factorsTranscriptome analysisColon cancerColon cancer metastasisReduction of liver metastasisDownstream targetsCell differentiation
2019
Functional Diversity of Myeloid-Derived Suppressor Cells: The Multitasking Hydra of Cancer.
Jayakumar A, Bothwell ALM. Functional Diversity of Myeloid-Derived Suppressor Cells: The Multitasking Hydra of Cancer. The Journal Of Immunology 2019, 203: 1095-1103. PMID: 31427398, PMCID: PMC6703177, DOI: 10.4049/jimmunol.1900500.Peer-Reviewed Original ResearchConceptsRegulatory B cellsRegulatory T cellsT cellsB cellsSuppressor cellsIL-17-producing T cellsAntitumor T cellsB cell functionHost immune responseAbility of MDSCsAttractive immunotherapeutic targetDifferent tumor modelsMDSC functionSuppressive cellsIL-17Tumor cell survivalImmunotherapeutic targetImmunological nicheImmune responseTumor growthTumor modelCancer typesMDSCsCell functionMyeloidDickkopf1: An immunomodulatory ligand and Wnt antagonist in pathological inflammation
Chae WJ, Bothwell ALM. Dickkopf1: An immunomodulatory ligand and Wnt antagonist in pathological inflammation. Differentiation 2019, 108: 33-39. PMID: 31221431, PMCID: PMC6982462, DOI: 10.1016/j.diff.2019.05.003.Peer-Reviewed Original ResearchConceptsCell proliferationPro-inflammatory ligandsRole of DKK1Pro-inflammatory roleRepair processPoor disease outcomeOrgan homeostasisTransduction pathwaysCanonical WntCell differentiationTissue repair processMulticellular interactionsOrgan injuryCell typesInflammatory diseasesTissue injuryDisease outcomeImmune responseWntBone diseaseWnt antagonistsPathological inflammationMusculoskeletal diseasesExpression levelsDickkopf1Ripk3-induced inflammation by I-MDSCs promotes intestinal tumors
Jayakumar A, Bothwell ALM. Ripk3-induced inflammation by I-MDSCs promotes intestinal tumors. Cancer Research 2019, 79: canres.2153.2018. PMID: 30786994, PMCID: PMC7395226, DOI: 10.1158/0008-5472.can-18-2153.Peer-Reviewed Original ResearchConceptsReceptor-interacting protein kinase 3I-MDSCsIntestinal tumorsIntestinal tumor modelTumor modelColorectal cancerT cellsKey inflammatory mechanismsAntitumor T cellsTransplantable tumor modelsPotential therapeutic targetPossible therapeutic interventionsI-MDSCMDSC subsetsInflammatory mechanismsMDSC functionSuppressor cellsTumor sizeInflammatory cytokinesMC38 tumorsCytokine synthesisMonocytic markersTherapeutic targetTumorigenic factorsTherapeutic interventions
2018
Canonical and Non-Canonical Wnt Signaling in Immune Cells
Chae WJ, Bothwell ALM. Canonical and Non-Canonical Wnt Signaling in Immune Cells. Trends In Immunology 2018, 39: 830-847. PMID: 30213499, PMCID: PMC7367500, DOI: 10.1016/j.it.2018.08.006.Peer-Reviewed Original ResearchRegulation of human T cell responses by dNP2-ctCTLA-4 inhibits human skin and microvessel graft rejection
Lim S, Kirkiles-Smith NC, Pober JS, Bothwell ALM, Choi JM. Regulation of human T cell responses by dNP2-ctCTLA-4 inhibits human skin and microvessel graft rejection. Biomaterials 2018, 183: 128-138. PMID: 30165256, PMCID: PMC6141312, DOI: 10.1016/j.biomaterials.2018.08.049.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell ProliferationCell-Penetrating PeptidesCTLA-4 AntigenCytokinesEndothelial CellsFemaleGraft RejectionHuman Umbilical Vein Endothelial CellsHumansLymphocyte ActivationMice, Inbred BALB CMice, KnockoutMice, SCIDMicrovesselsReceptors, ChemokineSkinSkin TransplantationT-LymphocytesConceptsT cell responsesHuman T cell responsesT cell infiltrationHuman T cellsT cellsCell responsesGraft rejectionCell infiltrationSCID/beige miceCell-permeable peptideBlood cytokine levelsT cell alloresponsesCD8 T cellsChemokine receptor expressionGranzyme B expressionAlloreactive T cellsSignificant side effectsDouble knockout miceHuman T cell activationBcl-2-transduced human umbilical vein endothelial cellsT cell activationHuman umbilical vein endothelial cellsUmbilical vein endothelial cellsSystemic immunosuppressantsAllograft rejectionIntranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice
Moon JS, Mun CH, Kim JH, Cho JY, Park SD, Park TY, Shin JS, Ho CC, Park YB, Ghosh S, Bothwell ALM, Lee SW, Lee SK. Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice. Kidney International 2018, 93: 1118-1130. PMID: 29409726, DOI: 10.1016/j.kint.2017.11.017.Peer-Reviewed Original ResearchMeSH KeywordsActive Transport, Cell NucleusAnimalsAnti-Inflammatory AgentsCell NucleusCellular MicroenvironmentCytokinesDisease Models, AnimalFemaleInflammation MediatorsKidneyLupus NephritisMice, Inbred NZBProtein DomainsRecombinant ProteinsSpleenT-Box Domain ProteinsT-Lymphocytes, Helper-InducerT-Lymphocytes, RegulatoryTranscription, GeneticConceptsLupus-prone miceTranscription modulation domainSystemic lupus erythematosusCell subsetsTh1-mediated autoimmune diseasesNucleus-transducible formNumber of Th1Severity of nephritisT cell subsetsT cell activationProinflammatory microenvironmentTh17 cellsTreg cellsImmunosuppressive cytokinesLupus patientsLupus erythematosusAutoimmune diseasesImmune therapeuticsF1 miceCell activationExcessive expressionMiceTbetMarked increaseMethylprednisolone
2017
Membrane‐bound Dickkopf‐1 in Foxp3+ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis
Chae W, Park J, Henegariu O, Yilmaz S, Hao L, Bothwell ALM. Membrane‐bound Dickkopf‐1 in Foxp3+ regulatory T cells suppresses T‐cell‐mediated autoimmune colitis. Immunology 2017, 152: 265-275. PMID: 28556921, PMCID: PMC5588763, DOI: 10.1111/imm.12766.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnimalsAutoimmune DiseasesAutoimmunityCell MembraneCell ProliferationCHO CellsColitisColonCricetulusDisease Models, AnimalDNA-Binding ProteinsForkhead Transcription FactorsGenetic Predisposition to DiseaseIntercellular Signaling Peptides and ProteinsLymphocyte ActivationMice, Inbred C57BLMice, KnockoutMitogen-Activated Protein KinasesPhenotypeSelf ToleranceSignal TransductionTime FactorsT-Lymphocytes, RegulatoryTransfectionConceptsRegulatory T cellsTreg cellsDKK-1 expressionAutoimmune colitisDickkopf-1T cellsT cell-mediated toleranceEffector CD4 T cellsCD4 T cellsInduction of toleranceT cell proliferationT cell receptor stimulationNovel TregColitis modelImmunological homeostasisImmunological toleranceFoxp3Receptor stimulationCanonical Wnt pathwayColitisFunctional inhibitionMonoclonal antibodiesDe novo protein synthesisProtein kinase pathwaySuppressor functionStat6 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 mediators
2016
Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation
Park HJ, Park HS, Lee JU, Bothwell AL, Choi JM. Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation. International Journal Of Molecular Sciences 2016, 17: 1347. PMID: 27548145, PMCID: PMC5000743, DOI: 10.3390/ijms17081347.Peer-Reviewed Original ResearchConceptsEffector T cell differentiationT cellsT cell differentiationAdaptive immunityFemale T cellsMale T cellsPeroxisome proliferator-activated receptor gammaIL-17 productionDifferentiation of Th1PPARγ agonist pioglitazoneProliferator-activated receptor gammaNaïve T cellsSplenic T cellsMouse splenic T cellsImportant immune regulatorPioglitazone treatmentTfh responsesTh17 cellsAgonist pioglitazoneTreg functionAutoimmune diseasesEstrogen exposureImmune regulatorsCell differentiationTh1Gender-specific differences in PPARγ regulation of follicular helper T cell responses with estrogen
Park HJ, Park HS, Lee JU, Bothwell AL, Choi JM. Gender-specific differences in PPARγ regulation of follicular helper T cell responses with estrogen. Scientific Reports 2016, 6: 28495. PMID: 27335315, PMCID: PMC4917844, DOI: 10.1038/srep28495.Peer-Reviewed Original ResearchConceptsFollicular helper T cell responsesHelper T cell responsesT cell responsesCell responsesTfh cellsT cellsGC responseMale T cellsPeroxisome proliferator-activated receptor gammaTfh cell responsesEffector T cellsPPARγ agonist pioglitazoneProliferator-activated receptor gammaT cell regulationWild-type miceRole of PPARγGerminal center B cellsT cell activationGender-specific differencesTfh responsesAgonist pioglitazoneAutoimmune diseasesMenstrual cycleFemale miceMale miceThe Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation
Chae WJ, Ehrlich AK, Chan PY, Teixeira AM, Henegariu O, Hao L, Shin JH, Park JH, Tang WH, Kim ST, Maher SE, Goldsmith-Pestana K, Shan P, Hwa J, Lee PJ, Krause DS, Rothlin CV, McMahon-Pratt D, Bothwell AL. The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity 2016, 44: 246-258. PMID: 26872695, PMCID: PMC4758884, DOI: 10.1016/j.immuni.2016.01.008.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, DermatophagoidesAntigens, ProtozoanAsthmaBlood PlateletsCell DifferentiationCells, CulturedCytokinesExtracellular Signal-Regulated MAP KinasesGene Expression RegulationHumansInflammationIntercellular Signaling Peptides and ProteinsLeishmania majorLeishmaniasis, CutaneousMiceMice, Inbred BALB CMice, Inbred C57BLMice, TransgenicModels, AnimalPyroglyphidaeSignal TransductionTh2 CellsTOR Serine-Threonine KinasesWnt ProteinsConceptsCell-mediated inflammationTh2 cell cytokine productionCell cytokine productionLeukocyte-platelet aggregatesLeukocyte infiltrationDkk-1Cytokine productionT helper 2 cellsLeishmania major infectionHouse dust miteTranscription factor c-MafAllergen challengeMajor infectionDust miteImmune responseDickkopf-1Parasitic infectionsGATA-3Pathological roleFunctional inhibitionInflammationC-MafP38 MAPKInfiltrationInfection
2015
dNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis
Lim S, Kim WJ, Kim YH, Lee S, Koo JH, Lee JA, Yoon H, Kim DH, Park HJ, Kim HM, Lee HG, Yun Kim J, Lee JU, Hun Shin J, Kyun Kim L, Doh J, Kim H, Lee SK, Bothwell AL, Suh M, Choi JM. dNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis. Nature Communications 2015, 6: 8244. PMID: 26372309, PMCID: PMC4579786, DOI: 10.1038/ncomms9244.Peer-Reviewed Original ResearchConceptsExperimental autoimmune encephalomyelitisMultiple sclerosisT cellsAutoimmune encephalomyelitisCytotoxic T-lymphocyte antigen-4T-lymphocyte antigen-4T helper 17 (Th17) cellsCNS inflammatory diseasesTherapeutic mouse modelsEffector T cellsHelper 17 cellsT helper 1Blood-brain barrierCentral nervous systemHuman T cellsHelper 1Antigen-4Inflammatory diseasesMouse modelNervous systemCurrent drugsResident cellsBrain tissueEffective agentCell-permeable peptideSpontaneous Intestinal Tumorigenesis in Apc/Min+ Mice Requires Altered T Cell Development with IL‐17A
Chae WJ, Bothwell AL. Spontaneous Intestinal Tumorigenesis in Apc/Min+ Mice Requires Altered T Cell Development with IL‐17A. Journal Of Immunology Research 2015, 2015: 860106. PMID: 26146642, PMCID: PMC4469837, DOI: 10.1155/2015/860106.Peer-Reviewed Original ResearchConceptsApc miceGATA-3 expressionIntestinal tumorigenesisFamilial adenomatous polyposisT cell developmentAdoptive transferIL-17AT cellsFunctional regulatory T cellsNaïve CD4 T cellsFrequency of Foxp3Regulatory T cellsAbility of TregsGene mutationsCD4 T cellsSpontaneous intestinal tumorigenesisWild-type TregsHuman familial adenomatous polyposisApc mouse modelAPC gene mutationsCell developmentAltered T cell developmentInflammatory diseasesTregsLamina propria
2014
The Immunotherapeutic Role of Regulatory T Cells in Leishmania (Viannia) panamensis Infection
Ehrlich A, Castilho TM, Goldsmith-Pestana K, Chae WJ, Bothwell AL, Sparwasser T, McMahon-Pratt D. The Immunotherapeutic Role of Regulatory T Cells in Leishmania (Viannia) panamensis Infection. The Journal Of Immunology 2014, 193: 2961-2970. PMID: 25098291, PMCID: PMC4170189, DOI: 10.4049/jimmunol.1400728.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodiesAntigen-Antibody ComplexCell ProliferationFemaleImmunotherapy, AdoptiveIndoleamine-Pyrrole 2,3,-DioxygenaseInflammationInterferon-gammaInterleukin-10Interleukin-13Interleukin-17Interleukin-2Leishmania guyanensisLeishmaniasis, MucocutaneousLymphocyte CountMiceMice, Inbred BALB CMice, TransgenicParasite LoadT-Lymphocytes, RegulatoryTransforming Growth Factor betaConceptsRegulatory T cellsPanamensis infectionInflammatory responseT cellsLeishmania parasitesDisease pathologyImmunotherapeutic treatment approachesL. panamensis infectionsLeishmania panamensis infectionPercentage of TregsRIL-2/Th2 inflammatory responseIL-13 levelsParasite loadAlternate treatment strategiesT cell proliferationTreg functionalityDisease exacerbationAdoptive transferIL-17IL-10Naive miceCytokine responsesImmunotherapeutic roleCytokine productionPPARγ Negatively Regulates T Cell Activation to Prevent Follicular Helper T Cells and Germinal Center Formation
Park HJ, Kim DH, Choi JY, Kim WJ, Kim JY, Senejani AG, Hwang SS, Kim LK, Tobiasova Z, Lee GR, Craft J, Bothwell AL, Choi JM. PPARγ Negatively Regulates T Cell Activation to Prevent Follicular Helper T Cells and Germinal Center Formation. PLOS ONE 2014, 9: e99127. PMID: 24921943, PMCID: PMC4055678, DOI: 10.1371/journal.pone.0099127.Peer-Reviewed Original ResearchConceptsFollicular helper T cellsHelper T cellsT cellsGerminal center reactionTfh cellsSheep red blood cell immunizationRed blood cell immunizationCenter reactionPeroxisome proliferator-activated receptor gammaIL-21 expressionProliferator-activated receptor gammaWild-type T cellsType T cellsGerminal center formationGerminal center B cellsT cell activationCell immunizationAutoantibody productionGlomerular inflammationSignature cytokinesAdaptive immunityGerminal centersGlucose metabolismNF-κBB cellsA Humanized Mouse Model of Autoimmune Insulitis
Milam A, Maher SE, Gibson JA, Lebastchi J, Wen L, Ruddle NH, Herold KC, Bothwell AL. A Humanized Mouse Model of Autoimmune Insulitis. Diabetes 2014, 63: 1712-1724. PMID: 24478396, PMCID: PMC3994947, DOI: 10.2337/db13-1141.Peer-Reviewed Original ResearchConceptsT cellsDiabetic donorsInsulin stainingMouse modelAntigen-pulsed cellsAutoantigen-derived peptidesNOD mouse modelHumanized mouse modelType 1 diabetesPancreatic β-cellsT cell linesHuman T cellsIslet infiltrationAutoimmune diabetesNOD-SCIDAutoimmune insulitisHuman diabetesDestructive infiltrationMouse isletsMechanism of inductionΒ-cellsDiabetesDiabetes researchDisease modelsInsulitisInterplay between DNA repair and inflammation, and the link to cancer
Kidane D, Chae WJ, Czochor J, Eckert KA, Glazer PM, Bothwell AL, Sweasy JB. Interplay between DNA repair and inflammation, and the link to cancer. Critical Reviews In Biochemistry And Molecular Biology 2014, 49: 116-139. PMID: 24410153, PMCID: PMC4300235, DOI: 10.3109/10409238.2013.875514.Peer-Reviewed Original ResearchMutation of POLB Causes Lupus in Mice
Senejani AG, Liu Y, Kidane D, Maher SE, Zeiss CJ, Park HJ, Kashgarian M, McNiff JM, Zelterman D, Bothwell AL, Sweasy JB. Mutation of POLB Causes Lupus in Mice. Cell Reports 2014, 6: 1-8. PMID: 24388753, PMCID: PMC3916967, DOI: 10.1016/j.celrep.2013.12.017.Peer-Reviewed Original ResearchConceptsSystemic lupus erythematosusLupus-like diseaseLupus erythematosusAutoimmune pathologyMouse modelGenome-wide association studiesPol β activityDecreased expressionMutant miceUnderlying causeMicePrevious genome-wide association studyΒ activityDNA polymerase activityReplication studyExcision repair pathwayImmune diversitySomatic hypermutationBase excision repair pathwayAssociation studiesErythematosusLupusPolymerase activityExpressionKey enzyme
2013
An electrospun scaffold integrating nucleic acid delivery for treatment of full-thickness wounds
Kobsa S, Kristofik NJ, Sawyer AJ, Bothwell AL, Kyriakides TR, Saltzman WM. An electrospun scaffold integrating nucleic acid delivery for treatment of full-thickness wounds. Biomaterials 2013, 34: 3891-3901. PMID: 23453058, PMCID: PMC3625647, DOI: 10.1016/j.biomaterials.2013.02.016.Peer-Reviewed Original Research