title: Anti-inflammatory potential of PI3Kδ and JAK inhibitors in asthma patients.
abstract: Phosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation. We have investigated the anti-inflammatory effects of PI3Kδ and JAK inhibition on cytokine release from asthma bronchoalveolar lavage (BAL) cells and T-cell activation, and measured lung PI3Kδ and JAK signalling pathway expression.
  
  
  
  Cells isolated from asthma patients and healthy subjects were treated with PI3Kδ or JAK inhibitors, and/or dexamethasone, before T-cell receptor stimulation. Levels of IFNγ, IL-13 and IL-17 were measured by ELISA and flow cytometry was used to assess T-cell activation. PI3Kδ, PI3Kγ, phosphorylated protein kinase B (pAKT) and Signal Transducer and Activator of Transcription (STAT) protein expression were assessed by immunohistochemistry in bronchial biopsy tissue from asthma patients and healthy subjects. PI3Kδ expression in BAL CD3 cells was measured by flow cytometry.
  
  
  
  JAK and PI3Kδ inhibitors reduced cytokine levels from both asthma and healthy BAL cells. Combining dexamethasone with either a JAK or PI3Kδ inhibitor showed an additive anti-inflammatory effect. JAK and PI3Kδ inhibitors were shown to have direct effects on T-cell activation. Immunohistochemistry showed increased numbers of PI3Kδ expressing cells in asthma bronchial tissue compared to controls. Asthma CD3 cells in BAL expressed higher levels of PI3Kδ protein compared to healthy cells.
  
  
  
  Targeting PI3Kδ or JAK may prove effective in reducing T-cell activation and the resulting cytokine production in asthma.
authors.affiliation: The University of Manchester; Division of Infection, Immunity & Respiratory Medicine; Manchester Academic Health Science Centre; University Hospital South Manchester NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK. tsouthworth@meu.org.uk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Southworth
authors.affiliation: The University of Manchester; Division of Infection, Immunity & Respiratory Medicine; Manchester Academic Health Science Centre; University Hospital South Manchester NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Plumb
authors.affiliation: The University of Manchester; Division of Infection, Immunity & Respiratory Medicine; Manchester Academic Health Science Centre; University Hospital South Manchester NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK.
authors.forename: Vandana
authors.initials: V
authors.lastname: Gupta
authors.affiliation: The University of Manchester; Division of Infection, Immunity & Respiratory Medicine; Manchester Academic Health Science Centre; University Hospital South Manchester NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK.
authors.forename: James
authors.initials: J
authors.lastname: Pearson
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ramis
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Lehner
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
authors.affiliation: The University of Manchester; Division of Infection, Immunity & Respiratory Medicine; Manchester Academic Health Science Centre; University Hospital South Manchester NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D017252:CD3 Complex / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D000075242:Janus Kinase Inhibitors / Q000494:pharmacology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010880:Piperidines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D017252:CD3 Complex; C573415:IFNG protein, human; C578095:IL13 protein, human; D018836:Inflammation Mediators; D018793:Interleukin-13; D020381:Interleukin-17; D000075242:Janus Kinase Inhibitors; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D003907:Dexamethasone; D007371:Interferon-gamma; C479163:tofacitinib; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; D053612:Janus Kinases
keywords: Asthma; Bronchoscopy; JAK/STAT; Phosphatidylinositol 3-kinase delta; T-cell cytokines