β1-Adrenoceptor autoantibodies from DCM patients enhance the proliferation of T lymphocytes through the β1-AR/cAMP/PKA and p38 MAPK pathways
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...
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| creator | Du, Yunhui Yan, Li Wang, Jin Zhan, Wenzhang Song, Kai Han, Xue Li, Xiao Cao, Jimin Liu, Huirong |
| description | 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.
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.
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.
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. |
| doi_str_mv | 10.1371/journal.pone.0052911 |
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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.
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.
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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0052911</identifier><identifier>PMID: 23300817</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adrenergic beta-1 Receptor Antagonists - pharmacology ; Adrenergic beta-Agonists - pharmacology ; Adrenergic receptors ; Aged ; Animals ; Antigens ; Autoantibodies ; Autoantibodies - blood ; Autoantibodies - metabolism ; Beta blockers ; Biology ; Cardiomyopathy ; Cardiomyopathy, Dilated - immunology ; Cardiomyopathy, Dilated - metabolism ; CD3 antigen ; Cell growth ; Cell proliferation ; Cell Proliferation - drug effects ; Cholecystokinin ; Cyclic AMP ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Cytokines ; Cytometry ; Diabetes ; Dilated cardiomyopathy ; Enzyme-linked immunosorbent assay ; Female ; Flow cytometry ; Gene expression ; Health care ; Heart ; Heart diseases ; Heart failure ; Hospitals ; Humans ; Imidazoles - pharmacology ; Inhibitors ; Interferon ; Interferon-gamma - metabolism ; Interleukin 4 ; Internal medicine ; Isoproterenol - pharmacology ; Isoquinolines - pharmacology ; Kinases ; Laboratory animals ; Lymphocytes ; Lymphocytes T ; Male ; MAP kinase ; Medicine ; Metoprolol ; Metoprolol - pharmacology ; Middle Aged ; p38 Mitogen-Activated Protein Kinases - metabolism ; Patients ; Phosphorylation ; Phosphorylation - drug effects ; Physiology ; Protein kinase A ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Pyridines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta-1 - immunology ; Receptors, Adrenergic, beta-1 - metabolism ; Rodents ; Signal Transduction - drug effects ; Signal Transduction - immunology ; Sulfonamides - pharmacology ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; Western blotting ; γ-Interferon</subject><ispartof>PloS one, 2012-12, Vol.7 (12), p.e52911-e52911</ispartof><rights>2012 Du et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Du et al 2012 Du et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4411-ea686beba40226debeb57341705dca78df8ffdb253609519cc71c2249d1c42e23</citedby><cites>FETCH-LOGICAL-c4411-ea686beba40226debeb57341705dca78df8ffdb253609519cc71c2249d1c42e23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534136/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534136/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23300817$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Hirsch, Emilio</contributor><creatorcontrib>Du, Yunhui</creatorcontrib><creatorcontrib>Yan, Li</creatorcontrib><creatorcontrib>Wang, Jin</creatorcontrib><creatorcontrib>Zhan, Wenzhang</creatorcontrib><creatorcontrib>Song, Kai</creatorcontrib><creatorcontrib>Han, Xue</creatorcontrib><creatorcontrib>Li, Xiao</creatorcontrib><creatorcontrib>Cao, Jimin</creatorcontrib><creatorcontrib>Liu, Huirong</creatorcontrib><title>β1-Adrenoceptor autoantibodies from DCM patients enhance the proliferation of T lymphocytes through the β1-AR/cAMP/PKA and p38 MAPK pathways</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.
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.
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.
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.</description><subject>Adrenergic beta-1 Receptor Antagonists - pharmacology</subject><subject>Adrenergic beta-Agonists - pharmacology</subject><subject>Adrenergic receptors</subject><subject>Aged</subject><subject>Animals</subject><subject>Antigens</subject><subject>Autoantibodies</subject><subject>Autoantibodies - blood</subject><subject>Autoantibodies - metabolism</subject><subject>Beta blockers</subject><subject>Biology</subject><subject>Cardiomyopathy</subject><subject>Cardiomyopathy, Dilated - immunology</subject><subject>Cardiomyopathy, Dilated - metabolism</subject><subject>CD3 antigen</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cholecystokinin</subject><subject>Cyclic AMP</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Cytokines</subject><subject>Cytometry</subject><subject>Diabetes</subject><subject>Dilated cardiomyopathy</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Gene expression</subject><subject>Health care</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Heart failure</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Inhibitors</subject><subject>Interferon</subject><subject>Interferon-gamma - metabolism</subject><subject>Interleukin 4</subject><subject>Internal medicine</subject><subject>Isoproterenol - pharmacology</subject><subject>Isoquinolines - pharmacology</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>MAP kinase</subject><subject>Medicine</subject><subject>Metoprolol</subject><subject>Metoprolol - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Du, Yunhui</au><au>Yan, Li</au><au>Wang, Jin</au><au>Zhan, Wenzhang</au><au>Song, Kai</au><au>Han, Xue</au><au>Li, Xiao</au><au>Cao, Jimin</au><au>Liu, Huirong</au><au>Hirsch, Emilio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>β1-Adrenoceptor autoantibodies from DCM patients enhance the proliferation of T lymphocytes through the β1-AR/cAMP/PKA and p38 MAPK pathways</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-12-31</date><risdate>2012</risdate><volume>7</volume><issue>12</issue><spage>e52911</spage><epage>e52911</epage><pages>e52911-e52911</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.
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.
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.
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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23300817</pmid><doi>10.1371/journal.pone.0052911</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-12, Vol.7 (12), p.e52911-e52911 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1327231499 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adrenergic beta-1 Receptor Antagonists - pharmacology Adrenergic beta-Agonists - pharmacology Adrenergic receptors Aged Animals Antigens Autoantibodies Autoantibodies - blood Autoantibodies - metabolism Beta blockers Biology Cardiomyopathy Cardiomyopathy, Dilated - immunology Cardiomyopathy, Dilated - metabolism CD3 antigen Cell growth Cell proliferation Cell Proliferation - drug effects Cholecystokinin Cyclic AMP Cyclic AMP-Dependent Protein Kinases - metabolism Cytokines Cytometry Diabetes Dilated cardiomyopathy Enzyme-linked immunosorbent assay Female Flow cytometry Gene expression Health care Heart Heart diseases Heart failure Hospitals Humans Imidazoles - pharmacology Inhibitors Interferon Interferon-gamma - metabolism Interleukin 4 Internal medicine Isoproterenol - pharmacology Isoquinolines - pharmacology Kinases Laboratory animals Lymphocytes Lymphocytes T Male MAP kinase Medicine Metoprolol Metoprolol - pharmacology Middle Aged p38 Mitogen-Activated Protein Kinases - metabolism Patients Phosphorylation Phosphorylation - drug effects Physiology Protein kinase A Protein Kinase Inhibitors - pharmacology Proteins Pyridines - pharmacology Rats Rats, Sprague-Dawley Receptors, Adrenergic, beta-1 - immunology Receptors, Adrenergic, beta-1 - metabolism Rodents Signal Transduction - drug effects Signal Transduction - immunology Sulfonamides - pharmacology T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism Western blotting γ-Interferon |
| title | β1-Adrenoceptor autoantibodies from DCM patients enhance the proliferation of T lymphocytes through the β1-AR/cAMP/PKA and p38 MAPK pathways |
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