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 rejectionTherapeutic Potential of Gene-Modified Regulatory T Cells: From Bench to Bedside
Chae WJ, Bothwell ALM. Therapeutic Potential of Gene-Modified Regulatory T Cells: From Bench to Bedside. Frontiers In Immunology 2018, 9: 303. PMID: 29503652, PMCID: PMC5820299, DOI: 10.3389/fimmu.2018.00303.Peer-Reviewed Original ResearchConceptsRegulatory T cellsInflammatory diseasesT cellsImmune responseEffective antitumor immune responseTherapeutic potentialT cell receptor specificityDysfunction of TregsField of TregsAberrant immune responseAdaptive immune cellsAntitumor immune responseInherent genetic defectsRecognition of antigenTreg functionChronic inflammationImmune cellsTregsImmune reactionsRecipients resultsTherapeutic approachesBasic research findingsOrgan donorsSuppressive functionImmune systemDKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation
Xiao Q, Wu J, Wang WJ, Chen S, Zheng Y, Yu X, Meeth K, Sahraei M, Bothwell ALM, Chen L, Bosenberg M, Chen J, Sexl V, Sun L, Li L, Tang W, Wu D. DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation. Nature Medicine 2018, 24: 262-270. PMID: 29431745, PMCID: PMC5840007, DOI: 10.1038/nm.4496.Peer-Reviewed Original ResearchMeSH KeywordsAdenomatous Polyposis Coli ProteinBeta CateninCD8-Positive T-LymphocytesCell Line, TumorColorectal NeoplasmsCytotoxicity, ImmunologicGene Expression Regulation, NeoplasticHumansIntercellular Signaling Peptides and ProteinsIntestinal NeoplasmsKiller Cells, NaturalLow Density Lipoprotein Receptor-Related Protein-5MelanomaProgrammed Cell Death 1 ReceptorPTEN PhosphohydrolaseSignal TransductionSTAT5 Transcription FactorTumor Escape
2016
The 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 peptide
2014
A 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 Research
2013
Neuroprotection against neuroblastoma cell death induced by depletion of mitochondrial glutathione
Dukhande VV, Kawikova I, Bothwell AL, Lai JC. Neuroprotection against neuroblastoma cell death induced by depletion of mitochondrial glutathione. Apoptosis 2013, 18: 702-712. PMID: 23494481, PMCID: PMC3645366, DOI: 10.1007/s10495-013-0836-4.Peer-Reviewed Original ResearchMeSH KeywordsApoptosisAzolesBcl-2-Associated X ProteinButhionine SulfoximineCell Line, TumorCell SurvivalCoculture TechniquesCytochromes cCytosolEthacrynic AcidGlioblastomaGlutathioneHumansIsoindolesMitochondriaNeuroblastomaNeuronsOrganoselenium CompoundsProto-Oncogene Proteins c-bcl-2Reactive Oxygen SpeciesConceptsSK-N-SH cellsMitochondrial glutathioneCell deathNeuroblastoma cell deathMitochondrial dysfunctionCellular reactive oxygen speciesMitochondrial glutathione poolPrevention of apoptosisMitochondrial glutathione depletionNeurodegenerative disordersOxidative stressGlutathione depletionReactive oxygen speciesGlutathione poolDistinct inhibitorsApoptotic deathGlutathione metabolismEthacrynic acidROS productionOxygen speciesBCL2 overexpressionGSH depletionApoptosisL-buthionineCellsAn 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
2012
The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases
Choi JM, Bothwell AL. The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases. Molecules And Cells 2012, 33: 217-222. PMID: 22382683, PMCID: PMC3887706, DOI: 10.1007/s10059-012-2297-y.Peer-Reviewed Original ResearchConceptsPeroxisome proliferator-activated receptorIndependent regulatory mechanismsImportant regulatory roleNuclear receptor proteinsT helper cell differentiationTranscription factorsCellular differentiationNuclear receptor peroxisome proliferator-activated receptorGene expressionRegulatory mechanismsDiverse rolesHelper cell differentiationT cell survivalPPARβ/δCell differentiationRegulatory roleImportant regulatorReceptor proteinNuclear receptorsT cell activationProliferator-activated receptorAutoimmune diseasesLigand treatmentProteinSynthetic ligands
2011
Risperidone-Related Improvement of Irritability in Children with Autism Is not Associated with Changes in Serum of Epidermal Growth Factor and Interleukin-13
Tobiasova Z, van der Lingen KH, Scahill L, Leckman JF, Zhang Y, Chae W, McCracken JT, McDougle CJ, Vitiello B, Tierney E, Aman MG, Arnold LE, Katsovich L, Hoekstra PJ, Volkmar F, Bothwell AL, Kawikova I. Risperidone-Related Improvement of Irritability in Children with Autism Is not Associated with Changes in Serum of Epidermal Growth Factor and Interleukin-13. Journal Of Child And Adolescent Psychopharmacology 2011, 21: 555-564. PMID: 22070180, PMCID: PMC3279715, DOI: 10.1089/cap.2010.0134.Peer-Reviewed Original ResearchConceptsMedication-free subjectsEpidermal growth factorHealthy controlsInflammatory markersIL-13IL-1 receptor antagonistGrowth factorSerum inflammatory markersChemoattractant protein-1Placebo groupClinical improvementBaseline visitIL-17Serum levelsCytokine concentrationsInflammatory moleculesSerum concentrationsClinical trialsHealthy subjectsIL-1Interleukin-13RisperidoneAltered levelsProtein 1Diagnosis of autismReperfusion Injury Intensifies the Adaptive Human T Cell Alloresponse in a Human-Mouse Chimeric Artery Model
Yi T, Fogal B, Hao Z, Tobiasova Z, Wang C, Rao DA, Al-Lamki RS, Kirkiles-Smith NC, Kulkarni S, Bradley JR, Bothwell AL, Sessa WC, Tellides G, Pober JS. Reperfusion Injury Intensifies the Adaptive Human T Cell Alloresponse in a Human-Mouse Chimeric Artery Model. Arteriosclerosis Thrombosis And Vascular Biology 2011, 32: 353-360. PMID: 22053072, PMCID: PMC3262100, DOI: 10.1161/atvbaha.111.239285.Peer-Reviewed Original ResearchConceptsArtery segmentsReperfusion injuryNonimmune injuryHuman artery segmentsHuman-mouse chimeric modelInfrarenal aortic interposition graftsT-cell-mediated injuryMouse hostHuman peripheral blood mononuclear cellsPeripheral blood mononuclear cellsCell-mediated injuryT cell alloresponseBlood mononuclear cellsAdaptive immune responsesAortic interposition graftsImmunodeficient mouse hostsGraft survivalInterposition graftImmunologic rejectionMononuclear cellsT cellsImmune responseMinimal sequelaeChimeric modelInjuryPeroxisome Proliferator–Activated Receptor-γ Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells
Tobiasova Z, Zhang L, Yi T, Qin L, Manes TD, Kulkarni S, Lorber MI, Rodriguez FC, Choi JM, Tellides G, Pober JS, Kawikova I, Bothwell AL. Peroxisome Proliferator–Activated Receptor-γ Agonists Prevent In Vivo Remodeling of Human Artery Induced by Alloreactive T Cells. Circulation 2011, 124: 196-205. PMID: 21690493, PMCID: PMC3347886, DOI: 10.1161/circulationaha.110.015396.Peer-Reviewed Original ResearchMeSH KeywordsAdoptive TransferAnilidesAnimalsArteriesCell MovementCell ProliferationCytokinesGraft RejectionHumansHypoglycemic AgentsImmunologic MemoryIsoantigensMiceMice, SCIDPioglitazonePPAR gammaProstaglandin D2SuperantigensThiazolidinedionesT-LymphocytesTransplantation, HeterologousTransplantation, HomologousConceptsT cell responsesMemory T cellsVascular graft rejectionT cellsPPARγ agonistsVascular rejectionGraft rejectionAllogeneic human peripheral blood mononuclear cellsHuman memory T-cell responsesHuman T cell responsesMemory T cell responsesHuman peripheral blood mononuclear cellsTranscription factor peroxisome proliferator-activated receptorPeripheral blood mononuclear cellsChronic graft lossPeroxisome proliferator-activated receptorT-cell infiltratesAllogeneic T cellsAlloreactive T cellsBlood mononuclear cellsAlloantigen-induced proliferationVascular cell activationHuman arteriesProliferator-activated receptorEffects of PPARγ
2010
Altered immunoglobulin profiles in children with Tourette syndrome
Bos-Veneman NG, Olieman R, Tobiasova Z, Hoekstra PJ, Katsovich L, Bothwell AL, Leckman JF, Kawikova I. Altered immunoglobulin profiles in children with Tourette syndrome. Brain Behavior And Immunity 2010, 25: 532-538. PMID: 21156204, PMCID: PMC3056238, DOI: 10.1016/j.bbi.2010.12.003.Peer-Reviewed Original ResearchConceptsTourette syndromeSymptom exacerbationHealthy controlsSymptom severityPost-infectious autoimmunityB cell immunityLevels of IgG2Independent cross-sectional samplesCell immunitySerum levelsAdditional patientsIgG3 levelsIgM levelsImmunoglobulin profileHealthy childrenImmune deficiencyTrend-level significanceHealthy subjectsSerum IgG3PatientsIg profilesCross-sectional sampleIgG3Time pointsIg concentrationsCell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation
Choi JM, Shin JH, Sohn MH, Harding MJ, Park JH, Tobiasova Z, Kim DY, Maher SE, Chae WJ, Park SH, Lee CG, Lee SK, Bothwell AL. Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 18575-18580. PMID: 20937878, PMCID: PMC2972952, DOI: 10.1073/pnas.1000400107.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAsthmaAutoimmune DiseasesCell Membrane PermeabilityDisease Models, AnimalFemaleForkhead Transcription FactorsHumansInflammatory Bowel DiseasesLymphocyte ActivationMaleMiceMice, Inbred BALB CMice, Inbred C57BLMice, KnockoutMice, Mutant StrainsRecombinant Fusion ProteinsT-Lymphocytes, RegulatoryConceptsAllergic airway inflammationT cellsAirway inflammationAllergic diseasesFOXP3 proteinOvalbumin-induced allergic airway inflammationWild-type CD4 T cellsAllergic disease modelsDevelopment of colitisInflammatory bowel diseaseRegulatory T cellsCD4 T cellsInflammatory immune responseT cell activationFoxP3 transductionBowel diseaseScurfy miceTreg functionAutoimmune diseasesAutoimmune symptomsIntranasal deliveryTherapeutic effectImmune responseSystemic deliveryClinical potential