title: Brain natriuretic peptide induces CD8+ T cell death via a caspase 3 associated pathway--implications following heart transplantation.
abstract: BACKGROUND
  Brain natriuretic peptide (BNP) remains elevated after cardiac transplantation despite replacement of the failing ventricle. Serum peaks are also seen during acute rejection episodes independent of intracardiac hemodynamic disturbance. High BNP levels are also reported during bacterial sepsis, burns, stroke and myocardial infarction. Given all of these conditions are linked by immune activation processes, we hypothesised that BNP is an immunoactive agent.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood of 40 cardiac transplant recipients. Cells were co-cultured for 72h in the presence or absence of BNP. Cells were then immunophenotyped using flow cytometry. Cell death pathways were determined using caspase 3 quantification and mitochondrial membrane assessment. Supernatants were analysed for cytokine, chemokine and growth factor production using luminex.
  
  
  RESULTS
  Co-culture of CD8+ T cells with BNP reduced cell number, and increased intracellular caspase 3. Supernatant analysis revealed that BNP reduced the expression of inflammatory cytokines including TNF-α, IL-1α and IL-6. However it preserved the production of anti-inflammatory and regulatory cytokines such as IL-4, 5 and 13.
  
  
  CONCLUSIONS
  Our findings provide evidence that BNP directly induces CD8+ T cell apoptosis via a caspase 3 associated mechanism from cardiac transplant patients. This may impart significant consequences on immune mediated disease processes, such as allograft rejection.
authors.affiliation: The Transplant Centre, University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Manchester, M23 9LT, UK. doctorshaw@doctors.org.uk
authors.forename: Steven M
authors.initials: SM
authors.lastname: Shaw
authors.forename: William R
authors.initials: WR
authors.lastname: Critchley
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Puchalka
authors.forename: Simon G
authors.initials: SG
authors.lastname: Williams
authors.forename: Nizar
authors.initials: N
authors.lastname: Yonan
authors.forename: James E
authors.initials: JE
authors.lastname: Fildes
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D053148:Caspase 3 / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D051336:Mitochondrial Membranes / Q000276:immunology / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000276:immunology*; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D020097:Natriuretic Peptide, Brain; C505407:CASP3 protein, human; D053148:Caspase 3