LY294002 inhibits interferon-gamma-stimulated inducible nitric oxide synthase expression in BV2 microglial cells
The current study examined the potential involvement of phosphatidylinositol 3 phosphate kinase (PI3K) in interferon-gamma (IFN-γ)-stimulated nitric oxide (NO) generation in BV2 murine microglial cells. We found that LY294002, a PI3K inhibitor, markedly reduced IFN-γ-induced morphological changes, N...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2004-06, Vol.318 (3), p.691-697 |
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| container_title | Biochemical and biophysical research communications |
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| creator | Hwang, So-Young Jung, Jae-Seob Lim, Soo-Jeong Kim, Joo-Young Kim, Tae-Hyun Cho, Kwan-Ho Han, Inn-Oc |
| description | The current study examined the potential involvement of phosphatidylinositol 3 phosphate kinase (PI3K) in interferon-gamma (IFN-γ)-stimulated nitric oxide (NO) generation in BV2 murine microglial cells. We found that LY294002, a PI3K inhibitor, markedly reduced IFN-γ-induced morphological changes, NO production, and cell death. The inhibitory effect of LY294002 on NO generation may be mediated through specific inhibition of signal transducer and activator-1 (STAT1) and NF-κB, which are activated by IFN-γ. Induction of the mRNA for IFN-γ-mediated interferon response factor (IRF-1) and inducible protein-10 (IP-10) was not significantly affected by LY294002, indicating that suppression of PI3K may not be sufficient for downregulation of these genes. Although it remains unclear how PI3K signaling is involved in IFN-γ-mediated inflammatory reactions in the brain, our findings provide some insight into the inflammatory mechanisms of IFN-γ in the brain and suggest that regulators of the PI3K pathway may act as anti-inflammatory agents in microglia. |
| doi_str_mv | 10.1016/j.bbrc.2004.04.082 |
| format | Article |
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We found that LY294002, a PI3K inhibitor, markedly reduced IFN-γ-induced morphological changes, NO production, and cell death. The inhibitory effect of LY294002 on NO generation may be mediated through specific inhibition of signal transducer and activator-1 (STAT1) and NF-κB, which are activated by IFN-γ. Induction of the mRNA for IFN-γ-mediated interferon response factor (IRF-1) and inducible protein-10 (IP-10) was not significantly affected by LY294002, indicating that suppression of PI3K may not be sufficient for downregulation of these genes. Although it remains unclear how PI3K signaling is involved in IFN-γ-mediated inflammatory reactions in the brain, our findings provide some insight into the inflammatory mechanisms of IFN-γ in the brain and suggest that regulators of the PI3K pathway may act as anti-inflammatory agents in microglia.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1016/j.bbrc.2004.04.082</identifier><identifier>PMID: 15144893</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cell Death - drug effects ; Cell Death - physiology ; Cell Line ; Chromones - pharmacology ; DNA-Binding Proteins - metabolism ; Drug Interactions ; Enzyme Activation - drug effects ; Enzyme Inhibitors - pharmacology ; Gene Expression - drug effects ; Interferon-gamma ; Interferon-gamma - antagonists & inhibitors ; Interferon-gamma - pharmacology ; LY294002 ; Mice ; Microglia ; Microglia - drug effects ; Microglia - enzymology ; Microglia - metabolism ; Morpholines - pharmacology ; NF-kappa B - metabolism ; Nitric oxide ; Nitric Oxide - antagonists & inhibitors ; Nitric Oxide - biosynthesis ; Nitric Oxide Synthase - antagonists & inhibitors ; Nitric Oxide Synthase - biosynthesis ; Nitric Oxide Synthase Type II ; Oncogene Protein v-akt ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphorylation ; Protein-Tyrosine Kinases - metabolism ; Retroviridae Proteins, Oncogenic - metabolism ; Signal Transduction - drug effects ; STAT1 Transcription Factor ; Trans-Activators - metabolism ; Tyrosine - metabolism</subject><ispartof>Biochemical and biophysical research communications, 2004-06, Vol.318 (3), p.691-697</ispartof><rights>2004 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c449t-7cf2c38f8fa2a09b349bf11d1671eb0391302461faca78b5520eaa440ea3cd933</citedby><cites>FETCH-LOGICAL-c449t-7cf2c38f8fa2a09b349bf11d1671eb0391302461faca78b5520eaa440ea3cd933</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0006291X04008162$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15144893$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hwang, So-Young</creatorcontrib><creatorcontrib>Jung, Jae-Seob</creatorcontrib><creatorcontrib>Lim, Soo-Jeong</creatorcontrib><creatorcontrib>Kim, Joo-Young</creatorcontrib><creatorcontrib>Kim, Tae-Hyun</creatorcontrib><creatorcontrib>Cho, Kwan-Ho</creatorcontrib><creatorcontrib>Han, Inn-Oc</creatorcontrib><title>LY294002 inhibits interferon-gamma-stimulated inducible nitric oxide synthase expression in BV2 microglial cells</title><title>Biochemical and biophysical research communications</title><addtitle>Biochem Biophys Res Commun</addtitle><description>The current study examined the potential involvement of phosphatidylinositol 3 phosphate kinase (PI3K) in interferon-gamma (IFN-γ)-stimulated nitric oxide (NO) generation in BV2 murine microglial cells. We found that LY294002, a PI3K inhibitor, markedly reduced IFN-γ-induced morphological changes, NO production, and cell death. The inhibitory effect of LY294002 on NO generation may be mediated through specific inhibition of signal transducer and activator-1 (STAT1) and NF-κB, which are activated by IFN-γ. Induction of the mRNA for IFN-γ-mediated interferon response factor (IRF-1) and inducible protein-10 (IP-10) was not significantly affected by LY294002, indicating that suppression of PI3K may not be sufficient for downregulation of these genes. Although it remains unclear how PI3K signaling is involved in IFN-γ-mediated inflammatory reactions in the brain, our findings provide some insight into the inflammatory mechanisms of IFN-γ in the brain and suggest that regulators of the PI3K pathway may act as anti-inflammatory agents in microglia.</description><subject>Animals</subject><subject>Cell Death - drug effects</subject><subject>Cell Death - physiology</subject><subject>Cell Line</subject><subject>Chromones - pharmacology</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug Interactions</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gene Expression - drug effects</subject><subject>Interferon-gamma</subject><subject>Interferon-gamma - antagonists & inhibitors</subject><subject>Interferon-gamma - pharmacology</subject><subject>LY294002</subject><subject>Mice</subject><subject>Microglia</subject><subject>Microglia - drug effects</subject><subject>Microglia - enzymology</subject><subject>Microglia - metabolism</subject><subject>Morpholines - pharmacology</subject><subject>NF-kappa B - metabolism</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - antagonists & inhibitors</subject><subject>Nitric Oxide - biosynthesis</subject><subject>Nitric Oxide Synthase - antagonists & inhibitors</subject><subject>Nitric Oxide Synthase - biosynthesis</subject><subject>Nitric Oxide Synthase Type II</subject><subject>Oncogene Protein v-akt</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphorylation</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Retroviridae Proteins, Oncogenic - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>STAT1 Transcription Factor</subject><subject>Trans-Activators - metabolism</subject><subject>Tyrosine - metabolism</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1r3EAMhofS0myT_IEcgk-9eSuNZ20P5NKGJC0s9NKW5jTMjOVEiz82M-OQ_PvY7EJvBSEJ9OhFeoW4QFgjYPllt3Yu-LUEUOslavlOrBA05BJBvRcrAChzqfHvifgU4w4AUZX6ozjBDSpV62Il9tt7qRWAzHh4ZMcpzk2i0FIYh_zB9r3NY-J-6myiZp41k2fXUTZwCuyz8YUbyuLrkB5tpIxe9oFi5HGY0ezbH5n17MP40LHtMk9dF8_Eh9Z2kc6P9VT8vr35df093_68-3H9dZt7pXTKK99KX9Rt3VppQbtCadciNlhWSA4KjQVIVWJrva1qt9lIIGuVmnPhG10Up-LzQXcfxqeJYjI9x-UCO9A4RSOhlHVVyRmUB3C-M8ZArdkH7m14NQhm8dnszOKzWXw2S9TL0uVRfXI9Nf9WjsbOwNUBoPnHZ6ZgomcaPDUcyCfTjPw__Tfk0Y-r</recordid><startdate>20040604</startdate><enddate>20040604</enddate><creator>Hwang, So-Young</creator><creator>Jung, Jae-Seob</creator><creator>Lim, Soo-Jeong</creator><creator>Kim, Joo-Young</creator><creator>Kim, Tae-Hyun</creator><creator>Cho, Kwan-Ho</creator><creator>Han, Inn-Oc</creator><general>Elsevier Inc</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>7T5</scope><scope>7TK</scope><scope>H94</scope></search><sort><creationdate>20040604</creationdate><title>LY294002 inhibits interferon-gamma-stimulated inducible nitric oxide synthase expression in BV2 microglial cells</title><author>Hwang, So-Young ; Jung, Jae-Seob ; Lim, Soo-Jeong ; Kim, Joo-Young ; Kim, Tae-Hyun ; Cho, Kwan-Ho ; Han, Inn-Oc</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c449t-7cf2c38f8fa2a09b349bf11d1671eb0391302461faca78b5520eaa440ea3cd933</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Cell Death - drug effects</topic><topic>Cell Death - physiology</topic><topic>Cell Line</topic><topic>Chromones - pharmacology</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Drug Interactions</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gene Expression - drug effects</topic><topic>Interferon-gamma</topic><topic>Interferon-gamma - antagonists & inhibitors</topic><topic>Interferon-gamma - pharmacology</topic><topic>LY294002</topic><topic>Mice</topic><topic>Microglia</topic><topic>Microglia - drug effects</topic><topic>Microglia - enzymology</topic><topic>Microglia - metabolism</topic><topic>Morpholines - pharmacology</topic><topic>NF-kappa B - metabolism</topic><topic>Nitric oxide</topic><topic>Nitric Oxide - antagonists & inhibitors</topic><topic>Nitric Oxide - biosynthesis</topic><topic>Nitric Oxide Synthase - antagonists & inhibitors</topic><topic>Nitric Oxide Synthase - biosynthesis</topic><topic>Nitric Oxide Synthase Type II</topic><topic>Oncogene Protein v-akt</topic><topic>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Phosphorylation</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Retroviridae Proteins, Oncogenic - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>STAT1 Transcription Factor</topic><topic>Trans-Activators - metabolism</topic><topic>Tyrosine - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hwang, So-Young</creatorcontrib><creatorcontrib>Jung, Jae-Seob</creatorcontrib><creatorcontrib>Lim, Soo-Jeong</creatorcontrib><creatorcontrib>Kim, Joo-Young</creatorcontrib><creatorcontrib>Kim, Tae-Hyun</creatorcontrib><creatorcontrib>Cho, Kwan-Ho</creatorcontrib><creatorcontrib>Han, Inn-Oc</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hwang, So-Young</au><au>Jung, Jae-Seob</au><au>Lim, Soo-Jeong</au><au>Kim, Joo-Young</au><au>Kim, Tae-Hyun</au><au>Cho, Kwan-Ho</au><au>Han, Inn-Oc</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>LY294002 inhibits interferon-gamma-stimulated inducible nitric oxide synthase expression in BV2 microglial cells</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>2004-06-04</date><risdate>2004</risdate><volume>318</volume><issue>3</issue><spage>691</spage><epage>697</epage><pages>691-697</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><abstract>The current study examined the potential involvement of phosphatidylinositol 3 phosphate kinase (PI3K) in interferon-gamma (IFN-γ)-stimulated nitric oxide (NO) generation in BV2 murine microglial cells. We found that LY294002, a PI3K inhibitor, markedly reduced IFN-γ-induced morphological changes, NO production, and cell death. The inhibitory effect of LY294002 on NO generation may be mediated through specific inhibition of signal transducer and activator-1 (STAT1) and NF-κB, which are activated by IFN-γ. Induction of the mRNA for IFN-γ-mediated interferon response factor (IRF-1) and inducible protein-10 (IP-10) was not significantly affected by LY294002, indicating that suppression of PI3K may not be sufficient for downregulation of these genes. 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| subjects | Animals Cell Death - drug effects Cell Death - physiology Cell Line Chromones - pharmacology DNA-Binding Proteins - metabolism Drug Interactions Enzyme Activation - drug effects Enzyme Inhibitors - pharmacology Gene Expression - drug effects Interferon-gamma Interferon-gamma - antagonists & inhibitors Interferon-gamma - pharmacology LY294002 Mice Microglia Microglia - drug effects Microglia - enzymology Microglia - metabolism Morpholines - pharmacology NF-kappa B - metabolism Nitric oxide Nitric Oxide - antagonists & inhibitors Nitric Oxide - biosynthesis Nitric Oxide Synthase - antagonists & inhibitors Nitric Oxide Synthase - biosynthesis Nitric Oxide Synthase Type II Oncogene Protein v-akt Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphorylation Protein-Tyrosine Kinases - metabolism Retroviridae Proteins, Oncogenic - metabolism Signal Transduction - drug effects STAT1 Transcription Factor Trans-Activators - metabolism Tyrosine - metabolism |
| title | LY294002 inhibits interferon-gamma-stimulated inducible nitric oxide synthase expression in BV2 microglial cells |
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