title: β1-Adrenoceptor autoantibodies from DCM patients enhance the proliferation of T lymphocytes through the β1-AR/cAMP/PKA and p38 MAPK pathways.
abstract: BACKGROUND
  Autoantibodies against the second extracellular loop of the β(1)-adrenergic receptor (β(1)-AA) not only contribute to increased susceptibility to heart failure, but also play a causative role in myocardial remodeling through their sympathomimetic-like effects that are induced upon binding to the β(1)-adrenergic receptor. However, their role in the function of T lymphocytes has never been previously investigated. Our present study was designed to determine whether β(1)-AA isolated from the sera of dilated cardiomyopathy (DCM) patients caused the proliferation of T cells and the secretion of cytokines.
  
  
  METHODS
  Blood samples were collected from 95 DCM patients as well as 95 healthy subjects, and β(1)-AA was detected using ELISA. The CD3(+)T lymphocytes were selected separately through flow cytometry and the effect of β(1)-AA on T lymphocyte proliferation was examined by CCK-8 kits and CFSE assay. Western blotting was used to analyze the expressions of phospho-VASP and phospho-p38 MAPK.
  
  
  RESULTS
  β(1)-AA enhanced the proliferation of T lymphocytes. This effect could be blocked by the selective β(1)-adrenergic receptor antagonist metoprolol, PKA inhibitor H89, and p38 MAPK inhibitor SB203580. Furthermore, the expression of the phosphorylated forms of phospho-VASP and phospho-p38 MAPK were markedly increased in the presence of β(1)-AA. β(1)-AA also inhibited the secretion of interferon-γ (IFN-γ) while promoting an increase in interleukin-4 (IL-4) levels.
  
  
  CONCLUSIONS
  These results demonstrate that β(1)-AA isolated from DCM patients binds to β(1)-AR on the surface of T cells, causing changes in T-cell proliferation and secretion through the β(1)-AR/cAMP/PKA and p38 MAPK pathways.
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Du
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Wenzhang
authors.initials: W
authors.lastname: Zhan
authors.forename: Kai
authors.initials: K
authors.lastname: Song
authors.forename: Xue
authors.initials: X
authors.lastname: Han
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.forename: Jimin
authors.initials: J
authors.lastname: Cao
authors.forename: Huirong
authors.initials: H
authors.lastname: Liu
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D001323:Autoantibodies; D007093:Imidazoles; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018342:Receptors, Adrenergic, beta-1; D013449:Sulfonamides; D007371:Interferon-gamma; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008790:Metoprolol; D007545:Isoproterenol; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093642:SB 203580