STAT1-mediated signal integration between IFNγ and LPS leads to increased EC and SMC activation and monocyte adhesion
Inflammation plays an important role in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of atherosclerosis. Signal transducer and activated transcription 1 (STAT1) has been identified as a point of convergence for the cross talk between the pro-infl...
Gespeichert in:
| Veröffentlicht in: | American Journal of Physiology: Cell Physiology 2011-06, Vol.300 (6), p.C1337-C1344 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | C1344 |
|---|---|
| container_issue | 6 |
| container_start_page | C1337 |
| container_title | American Journal of Physiology: Cell Physiology |
| container_volume | 300 |
| creator | Sikorski, Krzysztof Chmielewski, Stefan Przybyl, Lukasz Heemann, Uwe Wesoly, Joanna Baumann, Marcus Bluyssen, Hans A R |
| description | Inflammation plays an important role in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of atherosclerosis. Signal transducer and activated transcription 1 (STAT1) has been identified as a point of convergence for the cross talk between the pro-inflammatory cytokine interferon γ (IFNγ) and the Toll-like receptor-4 (TLR4) ligand LPS in immune cells. However, there is no information available on the role of STAT1 in TLR4-mediated progression of atherosclerosis and on potential synergism between lipopolysaccharides (LPS) and IFNγ signaling in cells from the vasculature. Cultured human microvascular endothelial cells (HMECs) exposed to LPS activated STAT1 in a delayed manner that was inhibited by cycloheximide treatment. Pretreatment of HMECs as well as primary vascular smooth muscle cells (VSMCs) with IFNγ followed by LPS resulted in a significant increase in STAT1 phosphorylation compared with both factors alone. Increased STAT1 protein levels, strictly mediated by IFNγ, correlated with the augmented STAT1 phosphorylation that was absent in TLR4(-/-) cells. As assessed by PCR, Western analysis, and ELISA, this coincided with increased expression of the chemokine interferon gamma-induced protein 10 kDa (IP-10) and the adhesion molecule ICAM-1 in a TLR4-dependent manner.The STAT1-inhibitor fludarabine markedly reduced these effects as well as IFNγ and LPS-dependent adhesion of U937 cells to endothelial cells, emphasizing the potential importance of STAT1 in the integration of both signals. With the established roles of IFNγ and TLRs in atherosclerotic pathology, the STAT1-dependent signal integration between IFNγ and TLR in ECs and VSMCs in response to exogenous and endogenous atherogenic ligands could result in amplification of pro-inflammatory responses in the damaged vessel and be a novel mechanism involved in the initiation and progression of atherosclerosis. |
| doi_str_mv | 10.1152/ajpcell.00276.2010 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_868999581</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>868999581</sourcerecordid><originalsourceid>FETCH-LOGICAL-c302t-15f28c2911f699bf769ed1462e8d5965f755d6d8ef9fe603096c87fcb4a914133</originalsourceid><addsrcrecordid>eNo9kMtOAjEUhhujEURfwIXpztVgTztTpktCQE3wkoDrSWlPccgwg9Oi8bl8D5_JIujqJP8tOR8hl8D6ABm_0auNwarqM8YHss8ZsCPSjQZPIJPimHSZkCKRkIoOOfN-xRhLuVSnpMNBpBIy6JL32Xw4h2SNttQBLfXlstYVLeuAy1aHsqnpAsMHYk3vJ4_fX1TXlk6fZ7RCbT0NTYyaFrWP3fHo1509xGtC-b6v76R1UzfmMyDV9hV9VM_JidOVx4vD7ZGXyXg-ukumT7f3o-E0MYLxEP9wPDdcATip1MINpEILqeSY20zJzA2yzEqbo1MOJRNMSZMPnFmkWkEKQvTI9X530zZvW_ShWJd-B03X2Gx9kctcKZXlEJN8nzRt432Lrti05Vq3nwWwYoe7OOAufnEXO9yxdHWY3y4iwv_KH1_xA0IvfQ8</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>868999581</pqid></control><display><type>article</type><title>STAT1-mediated signal integration between IFNγ and LPS leads to increased EC and SMC activation and monocyte adhesion</title><source>MEDLINE</source><source>American Physiological Society</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Sikorski, Krzysztof ; Chmielewski, Stefan ; Przybyl, Lukasz ; Heemann, Uwe ; Wesoly, Joanna ; Baumann, Marcus ; Bluyssen, Hans A R</creator><creatorcontrib>Sikorski, Krzysztof ; Chmielewski, Stefan ; Przybyl, Lukasz ; Heemann, Uwe ; Wesoly, Joanna ; Baumann, Marcus ; Bluyssen, Hans A R</creatorcontrib><description>Inflammation plays an important role in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of atherosclerosis. Signal transducer and activated transcription 1 (STAT1) has been identified as a point of convergence for the cross talk between the pro-inflammatory cytokine interferon γ (IFNγ) and the Toll-like receptor-4 (TLR4) ligand LPS in immune cells. However, there is no information available on the role of STAT1 in TLR4-mediated progression of atherosclerosis and on potential synergism between lipopolysaccharides (LPS) and IFNγ signaling in cells from the vasculature. Cultured human microvascular endothelial cells (HMECs) exposed to LPS activated STAT1 in a delayed manner that was inhibited by cycloheximide treatment. Pretreatment of HMECs as well as primary vascular smooth muscle cells (VSMCs) with IFNγ followed by LPS resulted in a significant increase in STAT1 phosphorylation compared with both factors alone. Increased STAT1 protein levels, strictly mediated by IFNγ, correlated with the augmented STAT1 phosphorylation that was absent in TLR4(-/-) cells. As assessed by PCR, Western analysis, and ELISA, this coincided with increased expression of the chemokine interferon gamma-induced protein 10 kDa (IP-10) and the adhesion molecule ICAM-1 in a TLR4-dependent manner.The STAT1-inhibitor fludarabine markedly reduced these effects as well as IFNγ and LPS-dependent adhesion of U937 cells to endothelial cells, emphasizing the potential importance of STAT1 in the integration of both signals. With the established roles of IFNγ and TLRs in atherosclerotic pathology, the STAT1-dependent signal integration between IFNγ and TLR in ECs and VSMCs in response to exogenous and endogenous atherogenic ligands could result in amplification of pro-inflammatory responses in the damaged vessel and be a novel mechanism involved in the initiation and progression of atherosclerosis.</description><identifier>ISSN: 0363-6143</identifier><identifier>EISSN: 1522-1563</identifier><identifier>DOI: 10.1152/ajpcell.00276.2010</identifier><identifier>PMID: 21346151</identifier><language>eng</language><publisher>United States</publisher><subject>Antineoplastic Agents - pharmacology ; Atherosclerosis - physiopathology ; Cell Adhesion - drug effects ; Cell Adhesion - physiology ; Cell Line ; Endothelial Cells - cytology ; Endothelial Cells - drug effects ; Endothelial Cells - physiology ; Gene Expression ; Humans ; Interferon-gamma - pharmacology ; Lipopolysaccharides - pharmacology ; Monocytes - cytology ; Monocytes - drug effects ; Monocytes - physiology ; Muscle, Smooth, Vascular - cytology ; Myocytes, Smooth Muscle - cytology ; Myocytes, Smooth Muscle - drug effects ; Myocytes, Smooth Muscle - physiology ; Phosphorylation ; Signal Transduction - physiology ; STAT1 Transcription Factor - genetics ; STAT1 Transcription Factor - metabolism ; Toll-Like Receptor 4 - genetics ; Vidarabine - analogs & derivatives ; Vidarabine - pharmacology</subject><ispartof>American Journal of Physiology: Cell Physiology, 2011-06, Vol.300 (6), p.C1337-C1344</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c302t-15f28c2911f699bf769ed1462e8d5965f755d6d8ef9fe603096c87fcb4a914133</citedby><cites>FETCH-LOGICAL-c302t-15f28c2911f699bf769ed1462e8d5965f755d6d8ef9fe603096c87fcb4a914133</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3026,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21346151$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sikorski, Krzysztof</creatorcontrib><creatorcontrib>Chmielewski, Stefan</creatorcontrib><creatorcontrib>Przybyl, Lukasz</creatorcontrib><creatorcontrib>Heemann, Uwe</creatorcontrib><creatorcontrib>Wesoly, Joanna</creatorcontrib><creatorcontrib>Baumann, Marcus</creatorcontrib><creatorcontrib>Bluyssen, Hans A R</creatorcontrib><title>STAT1-mediated signal integration between IFNγ and LPS leads to increased EC and SMC activation and monocyte adhesion</title><title>American Journal of Physiology: Cell Physiology</title><addtitle>Am J Physiol Cell Physiol</addtitle><description>Inflammation plays an important role in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of atherosclerosis. Signal transducer and activated transcription 1 (STAT1) has been identified as a point of convergence for the cross talk between the pro-inflammatory cytokine interferon γ (IFNγ) and the Toll-like receptor-4 (TLR4) ligand LPS in immune cells. However, there is no information available on the role of STAT1 in TLR4-mediated progression of atherosclerosis and on potential synergism between lipopolysaccharides (LPS) and IFNγ signaling in cells from the vasculature. Cultured human microvascular endothelial cells (HMECs) exposed to LPS activated STAT1 in a delayed manner that was inhibited by cycloheximide treatment. Pretreatment of HMECs as well as primary vascular smooth muscle cells (VSMCs) with IFNγ followed by LPS resulted in a significant increase in STAT1 phosphorylation compared with both factors alone. Increased STAT1 protein levels, strictly mediated by IFNγ, correlated with the augmented STAT1 phosphorylation that was absent in TLR4(-/-) cells. As assessed by PCR, Western analysis, and ELISA, this coincided with increased expression of the chemokine interferon gamma-induced protein 10 kDa (IP-10) and the adhesion molecule ICAM-1 in a TLR4-dependent manner.The STAT1-inhibitor fludarabine markedly reduced these effects as well as IFNγ and LPS-dependent adhesion of U937 cells to endothelial cells, emphasizing the potential importance of STAT1 in the integration of both signals. With the established roles of IFNγ and TLRs in atherosclerotic pathology, the STAT1-dependent signal integration between IFNγ and TLR in ECs and VSMCs in response to exogenous and endogenous atherogenic ligands could result in amplification of pro-inflammatory responses in the damaged vessel and be a novel mechanism involved in the initiation and progression of atherosclerosis.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>Atherosclerosis - physiopathology</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Adhesion - physiology</subject><subject>Cell Line</subject><subject>Endothelial Cells - cytology</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - physiology</subject><subject>Gene Expression</subject><subject>Humans</subject><subject>Interferon-gamma - pharmacology</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Monocytes - cytology</subject><subject>Monocytes - drug effects</subject><subject>Monocytes - physiology</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Myocytes, Smooth Muscle - cytology</subject><subject>Myocytes, Smooth Muscle - drug effects</subject><subject>Myocytes, Smooth Muscle - physiology</subject><subject>Phosphorylation</subject><subject>Signal Transduction - physiology</subject><subject>STAT1 Transcription Factor - genetics</subject><subject>STAT1 Transcription Factor - metabolism</subject><subject>Toll-Like Receptor 4 - genetics</subject><subject>Vidarabine - analogs & derivatives</subject><subject>Vidarabine - pharmacology</subject><issn>0363-6143</issn><issn>1522-1563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtOAjEUhhujEURfwIXpztVgTztTpktCQE3wkoDrSWlPccgwg9Oi8bl8D5_JIujqJP8tOR8hl8D6ABm_0auNwarqM8YHss8ZsCPSjQZPIJPimHSZkCKRkIoOOfN-xRhLuVSnpMNBpBIy6JL32Xw4h2SNttQBLfXlstYVLeuAy1aHsqnpAsMHYk3vJ4_fX1TXlk6fZ7RCbT0NTYyaFrWP3fHo1509xGtC-b6v76R1UzfmMyDV9hV9VM_JidOVx4vD7ZGXyXg-ukumT7f3o-E0MYLxEP9wPDdcATip1MINpEILqeSY20zJzA2yzEqbo1MOJRNMSZMPnFmkWkEKQvTI9X530zZvW_ShWJd-B03X2Gx9kctcKZXlEJN8nzRt432Lrti05Vq3nwWwYoe7OOAufnEXO9yxdHWY3y4iwv_KH1_xA0IvfQ8</recordid><startdate>20110601</startdate><enddate>20110601</enddate><creator>Sikorski, Krzysztof</creator><creator>Chmielewski, Stefan</creator><creator>Przybyl, Lukasz</creator><creator>Heemann, Uwe</creator><creator>Wesoly, Joanna</creator><creator>Baumann, Marcus</creator><creator>Bluyssen, Hans A R</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20110601</creationdate><title>STAT1-mediated signal integration between IFNγ and LPS leads to increased EC and SMC activation and monocyte adhesion</title><author>Sikorski, Krzysztof ; Chmielewski, Stefan ; Przybyl, Lukasz ; Heemann, Uwe ; Wesoly, Joanna ; Baumann, Marcus ; Bluyssen, Hans A R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c302t-15f28c2911f699bf769ed1462e8d5965f755d6d8ef9fe603096c87fcb4a914133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>Atherosclerosis - physiopathology</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell Adhesion - physiology</topic><topic>Cell Line</topic><topic>Endothelial Cells - cytology</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - physiology</topic><topic>Gene Expression</topic><topic>Humans</topic><topic>Interferon-gamma - pharmacology</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Monocytes - cytology</topic><topic>Monocytes - drug effects</topic><topic>Monocytes - physiology</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Myocytes, Smooth Muscle - cytology</topic><topic>Myocytes, Smooth Muscle - drug effects</topic><topic>Myocytes, Smooth Muscle - physiology</topic><topic>Phosphorylation</topic><topic>Signal Transduction - physiology</topic><topic>STAT1 Transcription Factor - genetics</topic><topic>STAT1 Transcription Factor - metabolism</topic><topic>Toll-Like Receptor 4 - genetics</topic><topic>Vidarabine - analogs & derivatives</topic><topic>Vidarabine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sikorski, Krzysztof</creatorcontrib><creatorcontrib>Chmielewski, Stefan</creatorcontrib><creatorcontrib>Przybyl, Lukasz</creatorcontrib><creatorcontrib>Heemann, Uwe</creatorcontrib><creatorcontrib>Wesoly, Joanna</creatorcontrib><creatorcontrib>Baumann, Marcus</creatorcontrib><creatorcontrib>Bluyssen, Hans A R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>American Journal of Physiology: Cell Physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sikorski, Krzysztof</au><au>Chmielewski, Stefan</au><au>Przybyl, Lukasz</au><au>Heemann, Uwe</au><au>Wesoly, Joanna</au><au>Baumann, Marcus</au><au>Bluyssen, Hans A R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>STAT1-mediated signal integration between IFNγ and LPS leads to increased EC and SMC activation and monocyte adhesion</atitle><jtitle>American Journal of Physiology: Cell Physiology</jtitle><addtitle>Am J Physiol Cell Physiol</addtitle><date>2011-06-01</date><risdate>2011</risdate><volume>300</volume><issue>6</issue><spage>C1337</spage><epage>C1344</epage><pages>C1337-C1344</pages><issn>0363-6143</issn><eissn>1522-1563</eissn><abstract>Inflammation plays an important role in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of atherosclerosis. Signal transducer and activated transcription 1 (STAT1) has been identified as a point of convergence for the cross talk between the pro-inflammatory cytokine interferon γ (IFNγ) and the Toll-like receptor-4 (TLR4) ligand LPS in immune cells. However, there is no information available on the role of STAT1 in TLR4-mediated progression of atherosclerosis and on potential synergism between lipopolysaccharides (LPS) and IFNγ signaling in cells from the vasculature. Cultured human microvascular endothelial cells (HMECs) exposed to LPS activated STAT1 in a delayed manner that was inhibited by cycloheximide treatment. Pretreatment of HMECs as well as primary vascular smooth muscle cells (VSMCs) with IFNγ followed by LPS resulted in a significant increase in STAT1 phosphorylation compared with both factors alone. Increased STAT1 protein levels, strictly mediated by IFNγ, correlated with the augmented STAT1 phosphorylation that was absent in TLR4(-/-) cells. As assessed by PCR, Western analysis, and ELISA, this coincided with increased expression of the chemokine interferon gamma-induced protein 10 kDa (IP-10) and the adhesion molecule ICAM-1 in a TLR4-dependent manner.The STAT1-inhibitor fludarabine markedly reduced these effects as well as IFNγ and LPS-dependent adhesion of U937 cells to endothelial cells, emphasizing the potential importance of STAT1 in the integration of both signals. With the established roles of IFNγ and TLRs in atherosclerotic pathology, the STAT1-dependent signal integration between IFNγ and TLR in ECs and VSMCs in response to exogenous and endogenous atherogenic ligands could result in amplification of pro-inflammatory responses in the damaged vessel and be a novel mechanism involved in the initiation and progression of atherosclerosis.</abstract><cop>United States</cop><pmid>21346151</pmid><doi>10.1152/ajpcell.00276.2010</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0363-6143 |
| ispartof | American Journal of Physiology: Cell Physiology, 2011-06, Vol.300 (6), p.C1337-C1344 |
| issn | 0363-6143 1522-1563 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_868999581 |
| source | MEDLINE; American Physiological Society; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Antineoplastic Agents - pharmacology Atherosclerosis - physiopathology Cell Adhesion - drug effects Cell Adhesion - physiology Cell Line Endothelial Cells - cytology Endothelial Cells - drug effects Endothelial Cells - physiology Gene Expression Humans Interferon-gamma - pharmacology Lipopolysaccharides - pharmacology Monocytes - cytology Monocytes - drug effects Monocytes - physiology Muscle, Smooth, Vascular - cytology Myocytes, Smooth Muscle - cytology Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - physiology Phosphorylation Signal Transduction - physiology STAT1 Transcription Factor - genetics STAT1 Transcription Factor - metabolism Toll-Like Receptor 4 - genetics Vidarabine - analogs & derivatives Vidarabine - pharmacology |
| title | STAT1-mediated signal integration between IFNγ and LPS leads to increased EC and SMC activation and monocyte adhesion |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T23%3A57%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=STAT1-mediated%20signal%20integration%20between%20IFN%CE%B3%20and%20LPS%20leads%20to%20increased%20EC%20and%20SMC%20activation%20and%20monocyte%20adhesion&rft.jtitle=American%20Journal%20of%20Physiology:%20Cell%20Physiology&rft.au=Sikorski,%20Krzysztof&rft.date=2011-06-01&rft.volume=300&rft.issue=6&rft.spage=C1337&rft.epage=C1344&rft.pages=C1337-C1344&rft.issn=0363-6143&rft.eissn=1522-1563&rft_id=info:doi/10.1152/ajpcell.00276.2010&rft_dat=%3Cproquest_cross%3E868999581%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=868999581&rft_id=info:pmid/21346151&rfr_iscdi=true |