The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells are mediated by heme oxygenase-1 and its product carbon monoxide
Heme oxygenase-1 (HO-1) is an enzyme that degrades heme into biliverdin, free iron, and carbon monoxide (CO). This enzyme is known to have cytoprotective and anti-inflammatory effects. In this study, we investigated whether roflumilast, a newly developed specific phosphodiesterase 4 (PDE4) inhibitor...
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| Veröffentlicht in: | Inflammation research 2005-12, Vol.54 (12), p.508-513 |
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| creator | Kwak, H J Song, J S No, Z S Song, J H Yang, S D Cheon, H G |
| description | Heme oxygenase-1 (HO-1) is an enzyme that degrades heme into biliverdin, free iron, and carbon monoxide (CO). This enzyme is known to have cytoprotective and anti-inflammatory effects. In this study, we investigated whether roflumilast, a newly developed specific phosphodiesterase 4 (PDE4) inhibitor, mediates some of its anti-inflammatory effects by blocking nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) via the induction of HO-1 expression in macrophages.
The expression of iNOS and HO-1 was analyzed by western blot analysis. The production of NO and TNF-alpha was assayed by Greiss and ELISA, respectively.
Roflumilast markedly suppressed LPS-induced NO and TNF-alpha production and these phenomena were correlated with the induction of HO-1 protein levels. Moreover, the inhibitory effects of roflumilast on NO production were abrogated by a HO-1 inhibitor and a CO scavenger. Tricarbonyldichlrororuthenium(II) dimer, a CO releasing molecule significantly suppressed NO production.
These results suggested that roflumilast exerts its anti-inflammatory effects in macrophages through a novel mechanism that involves the action of HO-1 and its product, CO. |
| doi_str_mv | 10.1007/s00011-005-1386-1 |
| format | Article |
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The expression of iNOS and HO-1 was analyzed by western blot analysis. The production of NO and TNF-alpha was assayed by Greiss and ELISA, respectively.
Roflumilast markedly suppressed LPS-induced NO and TNF-alpha production and these phenomena were correlated with the induction of HO-1 protein levels. Moreover, the inhibitory effects of roflumilast on NO production were abrogated by a HO-1 inhibitor and a CO scavenger. Tricarbonyldichlrororuthenium(II) dimer, a CO releasing molecule significantly suppressed NO production.
These results suggested that roflumilast exerts its anti-inflammatory effects in macrophages through a novel mechanism that involves the action of HO-1 and its product, CO.</description><identifier>ISSN: 1023-3830</identifier><identifier>EISSN: 1420-908X</identifier><identifier>DOI: 10.1007/s00011-005-1386-1</identifier><identifier>PMID: 16389572</identifier><language>eng</language><publisher>Switzerland: Springer Nature B.V</publisher><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors ; Aminopyridines - pharmacology ; Animals ; Benzamides - pharmacology ; Biliverdin ; Blotting, Western ; Carbon monoxide ; Carbon Monoxide - metabolism ; Cell Line ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Cyclopropanes - pharmacology ; Enzyme-Linked Immunosorbent Assay ; Enzymes ; Heme ; Heme oxygenase (decyclizing) ; Heme Oxygenase (Decyclizing) - metabolism ; Inflammation ; Inhibitors ; Lipopolysaccharides ; Lipopolysaccharides - pharmacology ; Macrophages ; Macrophages - cytology ; Macrophages - drug effects ; Macrophages - enzymology ; Macrophages - metabolism ; Mice ; Nitric oxide ; Nitric Oxide - metabolism ; Nitric-oxide synthase ; Organometallic Compounds - pharmacology ; Oxygenase ; Phosphodiesterase ; Phosphodiesterase IV ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-TNF ; Tumor necrosis factor-α</subject><ispartof>Inflammation research, 2005-12, Vol.54 (12), p.508-513</ispartof><rights>Birkhäuser Verlag, Basel 2005</rights><rights>Birkhäuser Verlag, Basel 2005.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-5845a7a87bc672b3aeff1ccb61769231ce0def7df5d9965c69a92ecfe50845243</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16389572$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kwak, H J</creatorcontrib><creatorcontrib>Song, J S</creatorcontrib><creatorcontrib>No, Z S</creatorcontrib><creatorcontrib>Song, J H</creatorcontrib><creatorcontrib>Yang, S D</creatorcontrib><creatorcontrib>Cheon, H G</creatorcontrib><title>The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells are mediated by heme oxygenase-1 and its product carbon monoxide</title><title>Inflammation research</title><addtitle>Inflamm Res</addtitle><description>Heme oxygenase-1 (HO-1) is an enzyme that degrades heme into biliverdin, free iron, and carbon monoxide (CO). This enzyme is known to have cytoprotective and anti-inflammatory effects. In this study, we investigated whether roflumilast, a newly developed specific phosphodiesterase 4 (PDE4) inhibitor, mediates some of its anti-inflammatory effects by blocking nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) via the induction of HO-1 expression in macrophages.
The expression of iNOS and HO-1 was analyzed by western blot analysis. The production of NO and TNF-alpha was assayed by Greiss and ELISA, respectively.
Roflumilast markedly suppressed LPS-induced NO and TNF-alpha production and these phenomena were correlated with the induction of HO-1 protein levels. Moreover, the inhibitory effects of roflumilast on NO production were abrogated by a HO-1 inhibitor and a CO scavenger. Tricarbonyldichlrororuthenium(II) dimer, a CO releasing molecule significantly suppressed NO production.
These results suggested that roflumilast exerts its anti-inflammatory effects in macrophages through a novel mechanism that involves the action of HO-1 and its product, CO.</description><subject>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</subject><subject>Aminopyridines - pharmacology</subject><subject>Animals</subject><subject>Benzamides - pharmacology</subject><subject>Biliverdin</subject><subject>Blotting, Western</subject><subject>Carbon monoxide</subject><subject>Carbon Monoxide - metabolism</subject><subject>Cell Line</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 4</subject><subject>Cyclopropanes - pharmacology</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Enzymes</subject><subject>Heme</subject><subject>Heme oxygenase (decyclizing)</subject><subject>Heme Oxygenase (Decyclizing) - metabolism</subject><subject>Inflammation</subject><subject>Inhibitors</subject><subject>Lipopolysaccharides</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Macrophages</subject><subject>Macrophages - cytology</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - enzymology</subject><subject>Macrophages - metabolism</subject><subject>Mice</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric-oxide synthase</subject><subject>Organometallic Compounds - pharmacology</subject><subject>Oxygenase</subject><subject>Phosphodiesterase</subject><subject>Phosphodiesterase IV</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-TNF</subject><subject>Tumor necrosis factor-α</subject><issn>1023-3830</issn><issn>1420-908X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kd2KFDEQhYMo7jr6AN5IUPAua346SfflsvgHC4Ks6F1Ip6udLN3JmHSD_VI-ozXOgCB4k4TiOydVdQh5LviV4Ny-qZxzIRjnmgnVGiYekEvRSM463n57iG8uFVOt4hfkSa33SLeylY_JhTCq7bSVl-TX3R5oTPvYxyWXjcI4QlgqzSMteZzWOU6-LjQnOsVDPuRpqz6EvS9xABbTsAYYaIpLiYHmn1ikh5KxukSUxEQ_X3-VprmyNMA0VeoL0BmG6BeU9Rvdwwyo275D8hWYoD4NNOL_ZxcafOnRac7pj_tT8mj0U4Vn53tHvrx7e3fzgd1-ev_x5vqWBaWbhem20d761vbBWNkrj2OJEHojrOmkEgH4AKMdRj10ndHBdL6TEEbQHJWyUTvy-uSLffxYoS5ujvU4gk-Q1-pMx7WwViP46h_wPq8lYW9OGtyykFIapF7-lxJGNhwphMQJCiXXWmB0hxJnXzYnuDvm7U55O8zbHfPGY0denI3XHvf6V3EOWP0GwfCn7Q</recordid><startdate>200512</startdate><enddate>200512</enddate><creator>Kwak, H J</creator><creator>Song, J S</creator><creator>No, Z S</creator><creator>Song, J H</creator><creator>Yang, S D</creator><creator>Cheon, H G</creator><general>Springer Nature B.V</general><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>3V.</scope><scope>7QL</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>200512</creationdate><title>The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells are mediated by heme oxygenase-1 and its product carbon monoxide</title><author>Kwak, H J ; Song, J S ; No, Z S ; Song, J H ; Yang, S D ; Cheon, H G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-5845a7a87bc672b3aeff1ccb61769231ce0def7df5d9965c69a92ecfe50845243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors</topic><topic>Aminopyridines - pharmacology</topic><topic>Animals</topic><topic>Benzamides - pharmacology</topic><topic>Biliverdin</topic><topic>Blotting, Western</topic><topic>Carbon monoxide</topic><topic>Carbon Monoxide - metabolism</topic><topic>Cell Line</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 4</topic><topic>Cyclopropanes - pharmacology</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Enzymes</topic><topic>Heme</topic><topic>Heme oxygenase (decyclizing)</topic><topic>Heme Oxygenase (Decyclizing) - metabolism</topic><topic>Inflammation</topic><topic>Inhibitors</topic><topic>Lipopolysaccharides</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Macrophages</topic><topic>Macrophages - cytology</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - enzymology</topic><topic>Macrophages - metabolism</topic><topic>Mice</topic><topic>Nitric oxide</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric-oxide synthase</topic><topic>Organometallic Compounds - pharmacology</topic><topic>Oxygenase</topic><topic>Phosphodiesterase</topic><topic>Phosphodiesterase IV</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Tumor necrosis factor-TNF</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kwak, H J</creatorcontrib><creatorcontrib>Song, J S</creatorcontrib><creatorcontrib>No, Z S</creatorcontrib><creatorcontrib>Song, J H</creatorcontrib><creatorcontrib>Yang, S D</creatorcontrib><creatorcontrib>Cheon, H G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Inflammation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kwak, H J</au><au>Song, J S</au><au>No, Z S</au><au>Song, J H</au><au>Yang, S D</au><au>Cheon, H G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells are mediated by heme oxygenase-1 and its product carbon monoxide</atitle><jtitle>Inflammation research</jtitle><addtitle>Inflamm Res</addtitle><date>2005-12</date><risdate>2005</risdate><volume>54</volume><issue>12</issue><spage>508</spage><epage>513</epage><pages>508-513</pages><issn>1023-3830</issn><eissn>1420-908X</eissn><abstract>Heme oxygenase-1 (HO-1) is an enzyme that degrades heme into biliverdin, free iron, and carbon monoxide (CO). This enzyme is known to have cytoprotective and anti-inflammatory effects. In this study, we investigated whether roflumilast, a newly developed specific phosphodiesterase 4 (PDE4) inhibitor, mediates some of its anti-inflammatory effects by blocking nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) via the induction of HO-1 expression in macrophages.
The expression of iNOS and HO-1 was analyzed by western blot analysis. The production of NO and TNF-alpha was assayed by Greiss and ELISA, respectively.
Roflumilast markedly suppressed LPS-induced NO and TNF-alpha production and these phenomena were correlated with the induction of HO-1 protein levels. Moreover, the inhibitory effects of roflumilast on NO production were abrogated by a HO-1 inhibitor and a CO scavenger. Tricarbonyldichlrororuthenium(II) dimer, a CO releasing molecule significantly suppressed NO production.
These results suggested that roflumilast exerts its anti-inflammatory effects in macrophages through a novel mechanism that involves the action of HO-1 and its product, CO.</abstract><cop>Switzerland</cop><pub>Springer Nature B.V</pub><pmid>16389572</pmid><doi>10.1007/s00011-005-1386-1</doi><tpages>6</tpages></addata></record> |
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| subjects | 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors Aminopyridines - pharmacology Animals Benzamides - pharmacology Biliverdin Blotting, Western Carbon monoxide Carbon Monoxide - metabolism Cell Line Cyclic Nucleotide Phosphodiesterases, Type 4 Cyclopropanes - pharmacology Enzyme-Linked Immunosorbent Assay Enzymes Heme Heme oxygenase (decyclizing) Heme Oxygenase (Decyclizing) - metabolism Inflammation Inhibitors Lipopolysaccharides Lipopolysaccharides - pharmacology Macrophages Macrophages - cytology Macrophages - drug effects Macrophages - enzymology Macrophages - metabolism Mice Nitric oxide Nitric Oxide - metabolism Nitric-oxide synthase Organometallic Compounds - pharmacology Oxygenase Phosphodiesterase Phosphodiesterase IV Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-TNF Tumor necrosis factor-α |
| title | The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells are mediated by heme oxygenase-1 and its product carbon monoxide |
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