title: Carvedilol, a new antioxidative beta-blocker, blocks in vitro human peripheral blood T cell activation by downregulating NF-kappaB activity.
abstract: OBJECTIVE
  The activation of T lymphocytes contributes to the inflammatory process of atherosclerosis. Here we examined the effects of carvedilol, a new beta-blocker containing an antioxidative property, on the activation of T cells.
  
  
  METHODS
  Human peripheral blood T cells were negatively selected from whole blood. Cytokines were measured by ELISA. The NF-kappaB and related protein activity was determined by electrophoretic mobility shift assays, Western blotting, kinase assays and transfection assays.
  
  
  RESULTS
  Carvedilol was nontoxic at concentrations </=10 microM, however, higher dosages (>/=20 microM) induced T cell apoptosis. We demonstrated that carvedilol inhibited cytokine production from various stimuli-activated T cells. Carvedilol also suppressed the expression of T cell activation markers, including CD25, CD69 and CD71. Molecular investigation indicated that carvedilol specifically downregulated NF-kappaB but not activator protein 1 DNA-binding activity in activated T cells. The inhibitory effect was likely due to its antioxidative property. Meanwhile, carvedilol prevented stimuli-induced IkappaBalpha degradation. Such an effect was mediated through the inhibition of IkappaBalpha kinase activity. The inhibitory specificity on NF-kappaB by carvedilol was also demonstrated in transfection assays.
  
  
  CONCLUSIONS
  Our results demonstrated a novel therapeutic mechanism of carvedilol in atherosclerosis, namely the inhibition of T cell activation via downregulating NF-kappaB activity.
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003864:Depression, Chemical; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D019169:Jurkat Cells; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests / Q000379:methods; D011412:Propanolamines / Q000494:pharmacology*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011990:Receptors, Transferrin; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D000099192:CD69 Antigens
chemical_list: D000319:Adrenergic beta-Antagonists; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D000945:Antigens, Differentiation, T-Lymphocyte; D015415:Biomarkers; D002227:Carbazoles; D000077261:Carvedilol; D016207:Cytokines; D004247:DNA; D020672:I-kappa B Proteins; D037181:Lectins, C-Type; D016328:NF-kappa B; D011412:Propanolamines; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D018808:Transcription Factor AP-1; D000099192:CD69 Antigens; C068126:CD71 antigen