Glucocorticoids target suppressor of cytokine signaling 1 (SOCS1) and type 1 interferons to regulate Toll-like receptor-induced STAT1 activation
Endogenous and pharmacologic glucocorticoids (GCs) limit inflammatory cascades initiated by Toll-like receptor (TLR) activation. A long-standing clinical observation has been the delay between GC administration and the manifestation of GC's anti-inflammatory actions. We hypothesized that the GC...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2011-06, Vol.108 (23), p.9554-9559 |
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| creator | Bhattacharyya, Sandip Zhao, Yuxing Kay, Thomas W.H Muglia, Louis J |
| description | Endogenous and pharmacologic glucocorticoids (GCs) limit inflammatory cascades initiated by Toll-like receptor (TLR) activation. A long-standing clinical observation has been the delay between GC administration and the manifestation of GC's anti-inflammatory actions. We hypothesized that the GCs would have inhibitory effects that target late temporal pathways that propagate proinflammatory signals. Here we interrogated signal transducer and activator of transcription 1 (STAT1) regulation by GC and its consequences for cytokine production during activation of macrophages with TLR-specific ligands. We found that robust STAT1 activation does not occur until 2–3 h after TLR engagement, and that GC suppression of STAT1 phosphorylation first manifests at this time. GC attenuates TLR4-mediated STAT1 activation only through induction of suppressor of cytokine signaling 1 (SOCS1), which increases throughout the 6-h period after treatment. Inhibition of TLR3-mediated STAT1 activation occurs via two mechanisms, impairment of type I IFN secretion and induction of SOCS1. Our data show that SOCS1 and type I interferons are critical GC targets for regulating STAT1 activity and may account for overall GC effectiveness in inflammation suppression in the clinically relevant time frame. |
| doi_str_mv | 10.1073/pnas.1017296108 |
| format | Article |
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A long-standing clinical observation has been the delay between GC administration and the manifestation of GC's anti-inflammatory actions. We hypothesized that the GCs would have inhibitory effects that target late temporal pathways that propagate proinflammatory signals. Here we interrogated signal transducer and activator of transcription 1 (STAT1) regulation by GC and its consequences for cytokine production during activation of macrophages with TLR-specific ligands. We found that robust STAT1 activation does not occur until 2–3 h after TLR engagement, and that GC suppression of STAT1 phosphorylation first manifests at this time. GC attenuates TLR4-mediated STAT1 activation only through induction of suppressor of cytokine signaling 1 (SOCS1), which increases throughout the 6-h period after treatment. Inhibition of TLR3-mediated STAT1 activation occurs via two mechanisms, impairment of type I IFN secretion and induction of SOCS1. Our data show that SOCS1 and type I interferons are critical GC targets for regulating STAT1 activity and may account for overall GC effectiveness in inflammation suppression in the clinically relevant time frame.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1017296108</identifier><identifier>PMID: 21606371</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Blotting, Western ; Cell activation ; Cells, Cultured ; Cytokines ; Data processing ; Dexamethasone - pharmacology ; Effects ; Glucocorticoids ; Glucocorticoids - pharmacology ; Inflammation ; Interferon ; Interferon Regulatory Factor-3 - metabolism ; Interferon-alpha - metabolism ; Interferon-beta - pharmacology ; Interferons ; Interleukin-12 Subunit p40 - metabolism ; Interleukin-6 - metabolism ; Janus Kinase 2 - metabolism ; Ligands ; Lipopolysaccharides - pharmacology ; Macrophages ; Macrophages - cytology ; Macrophages - drug effects ; Macrophages - metabolism ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphorylation ; Phosphorylation - drug effects ; Physiological regulation ; Poly I-C - pharmacology ; Pretreatment ; Receptors, Interferon - metabolism ; Secretion ; Signal transduction ; SOCS-1 protein ; Stat1 protein ; STAT1 Transcription Factor - genetics ; STAT1 Transcription Factor - metabolism ; Suppressor of Cytokine Signaling 1 Protein ; Suppressor of Cytokine Signaling Proteins - genetics ; Suppressor of Cytokine Signaling Proteins - metabolism ; T cell receptors ; TLR3 protein ; Toll-like receptors ; Toll-Like Receptors - metabolism ; transactivators ; Transcription</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2011-06, Vol.108 (23), p.9554-9559</ispartof><rights>Copyright National Academy of Sciences Jun 7, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c587t-8671280b22ff62c720b476b5f39ca9b9beb98de06752e86373e16821e4009f773</citedby><cites>FETCH-LOGICAL-c587t-8671280b22ff62c720b476b5f39ca9b9beb98de06752e86373e16821e4009f773</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/108/23.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25831268$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25831268$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,728,781,785,804,886,27929,27930,53796,53798,58022,58255</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21606371$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bhattacharyya, Sandip</creatorcontrib><creatorcontrib>Zhao, Yuxing</creatorcontrib><creatorcontrib>Kay, Thomas W.H</creatorcontrib><creatorcontrib>Muglia, Louis J</creatorcontrib><title>Glucocorticoids target suppressor of cytokine signaling 1 (SOCS1) and type 1 interferons to regulate Toll-like receptor-induced STAT1 activation</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Endogenous and pharmacologic glucocorticoids (GCs) limit inflammatory cascades initiated by Toll-like receptor (TLR) activation. A long-standing clinical observation has been the delay between GC administration and the manifestation of GC's anti-inflammatory actions. We hypothesized that the GCs would have inhibitory effects that target late temporal pathways that propagate proinflammatory signals. Here we interrogated signal transducer and activator of transcription 1 (STAT1) regulation by GC and its consequences for cytokine production during activation of macrophages with TLR-specific ligands. We found that robust STAT1 activation does not occur until 2–3 h after TLR engagement, and that GC suppression of STAT1 phosphorylation first manifests at this time. GC attenuates TLR4-mediated STAT1 activation only through induction of suppressor of cytokine signaling 1 (SOCS1), which increases throughout the 6-h period after treatment. Inhibition of TLR3-mediated STAT1 activation occurs via two mechanisms, impairment of type I IFN secretion and induction of SOCS1. Our data show that SOCS1 and type I interferons are critical GC targets for regulating STAT1 activity and may account for overall GC effectiveness in inflammation suppression in the clinically relevant time frame.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Blotting, Western</subject><subject>Cell activation</subject><subject>Cells, Cultured</subject><subject>Cytokines</subject><subject>Data processing</subject><subject>Dexamethasone - pharmacology</subject><subject>Effects</subject><subject>Glucocorticoids</subject><subject>Glucocorticoids - pharmacology</subject><subject>Inflammation</subject><subject>Interferon</subject><subject>Interferon Regulatory Factor-3 - metabolism</subject><subject>Interferon-alpha - metabolism</subject><subject>Interferon-beta - pharmacology</subject><subject>Interferons</subject><subject>Interleukin-12 Subunit p40 - metabolism</subject><subject>Interleukin-6 - metabolism</subject><subject>Janus Kinase 2 - metabolism</subject><subject>Ligands</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Macrophages</subject><subject>Macrophages - cytology</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - metabolism</subject><subject>Mice</subject><subject>Mice, 129 Strain</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Physiological regulation</subject><subject>Poly I-C - pharmacology</subject><subject>Pretreatment</subject><subject>Receptors, Interferon - metabolism</subject><subject>Secretion</subject><subject>Signal transduction</subject><subject>SOCS-1 protein</subject><subject>Stat1 protein</subject><subject>STAT1 Transcription Factor - genetics</subject><subject>STAT1 Transcription Factor - metabolism</subject><subject>Suppressor of Cytokine Signaling 1 Protein</subject><subject>Suppressor of Cytokine Signaling Proteins - genetics</subject><subject>Suppressor of Cytokine Signaling Proteins - metabolism</subject><subject>T cell receptors</subject><subject>TLR3 protein</subject><subject>Toll-like receptors</subject><subject>Toll-Like Receptors - metabolism</subject><subject>transactivators</subject><subject>Transcription</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkstu1DAUhiMEoqWwZgVYbIBFqI-d-LJBqkZQkCp1MdO15ThO8DQTB9upNG_BI-PpDB1gw8rW8Xf-c_FfFC8BfwTM6fk06phvwIlkgMWj4hSwhJJVEj8uTjEmvBQVqU6KZzGuMcayFvhpcUKAYUY5nBY_L4fZeONDcsa7NqKkQ28TivM0BRujD8h3yGyTv3WjRdH1ox7c2CNA75fXiyV8QHpsUdpONofcmGzobPBjFvIo2H4edLJo5YehHNytzSFjp-RD6cZ2NrZFy9XFCpA2yd3p5Pz4vHjS6SHaF4fzrLj58nm1-FpeXV9-W1xclaYWPJWCcSACN4R0HSOGE9xUnDV1R6XRspGNbaRoLWa8JlbkWakFJgjYKi-h45yeFZ_2utPcbGxr7JiCHtQU3EaHrfLaqb9fRvdd9f5OUQAgvM4C7w4Cwf-YbUxq46Kxw6BH6-eoJObAKsHEf0nBgYqKVZDJt_-Qaz-HvPF7CASlbNf5-R4ywccYbPfQNGC1c4XauUIdXZEzXv856wP_2wYZeHMAdplHOaEIVbKuq0y82hPrmH_vqFALCuR-xoNCp73SfXBR3SwJzgUwSBCS0l9JcNEt</recordid><startdate>20110607</startdate><enddate>20110607</enddate><creator>Bhattacharyya, Sandip</creator><creator>Zhao, Yuxing</creator><creator>Kay, Thomas W.H</creator><creator>Muglia, Louis J</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110607</creationdate><title>Glucocorticoids target suppressor of cytokine signaling 1 (SOCS1) and type 1 interferons to regulate Toll-like receptor-induced STAT1 activation</title><author>Bhattacharyya, Sandip ; Zhao, Yuxing ; Kay, Thomas W.H ; Muglia, Louis J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c587t-8671280b22ff62c720b476b5f39ca9b9beb98de06752e86373e16821e4009f773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Biological Sciences</topic><topic>Blotting, Western</topic><topic>Cell activation</topic><topic>Cells, Cultured</topic><topic>Cytokines</topic><topic>Data processing</topic><topic>Dexamethasone - pharmacology</topic><topic>Effects</topic><topic>Glucocorticoids</topic><topic>Glucocorticoids - pharmacology</topic><topic>Inflammation</topic><topic>Interferon</topic><topic>Interferon Regulatory Factor-3 - metabolism</topic><topic>Interferon-alpha - metabolism</topic><topic>Interferon-beta - pharmacology</topic><topic>Interferons</topic><topic>Interleukin-12 Subunit p40 - metabolism</topic><topic>Interleukin-6 - metabolism</topic><topic>Janus Kinase 2 - metabolism</topic><topic>Ligands</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Macrophages</topic><topic>Macrophages - cytology</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - metabolism</topic><topic>Mice</topic><topic>Mice, 129 Strain</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Physiological regulation</topic><topic>Poly I-C - pharmacology</topic><topic>Pretreatment</topic><topic>Receptors, Interferon - metabolism</topic><topic>Secretion</topic><topic>Signal transduction</topic><topic>SOCS-1 protein</topic><topic>Stat1 protein</topic><topic>STAT1 Transcription Factor - genetics</topic><topic>STAT1 Transcription Factor - metabolism</topic><topic>Suppressor of Cytokine Signaling 1 Protein</topic><topic>Suppressor of Cytokine Signaling Proteins - genetics</topic><topic>Suppressor of Cytokine Signaling Proteins - metabolism</topic><topic>T cell receptors</topic><topic>TLR3 protein</topic><topic>Toll-like receptors</topic><topic>Toll-Like Receptors - metabolism</topic><topic>transactivators</topic><topic>Transcription</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bhattacharyya, Sandip</creatorcontrib><creatorcontrib>Zhao, Yuxing</creatorcontrib><creatorcontrib>Kay, Thomas W.H</creatorcontrib><creatorcontrib>Muglia, Louis J</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bhattacharyya, Sandip</au><au>Zhao, Yuxing</au><au>Kay, Thomas W.H</au><au>Muglia, Louis J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glucocorticoids target suppressor of cytokine signaling 1 (SOCS1) and type 1 interferons to regulate Toll-like receptor-induced STAT1 activation</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2011-06-07</date><risdate>2011</risdate><volume>108</volume><issue>23</issue><spage>9554</spage><epage>9559</epage><pages>9554-9559</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Endogenous and pharmacologic glucocorticoids (GCs) limit inflammatory cascades initiated by Toll-like receptor (TLR) activation. A long-standing clinical observation has been the delay between GC administration and the manifestation of GC's anti-inflammatory actions. We hypothesized that the GCs would have inhibitory effects that target late temporal pathways that propagate proinflammatory signals. Here we interrogated signal transducer and activator of transcription 1 (STAT1) regulation by GC and its consequences for cytokine production during activation of macrophages with TLR-specific ligands. We found that robust STAT1 activation does not occur until 2–3 h after TLR engagement, and that GC suppression of STAT1 phosphorylation first manifests at this time. GC attenuates TLR4-mediated STAT1 activation only through induction of suppressor of cytokine signaling 1 (SOCS1), which increases throughout the 6-h period after treatment. Inhibition of TLR3-mediated STAT1 activation occurs via two mechanisms, impairment of type I IFN secretion and induction of SOCS1. Our data show that SOCS1 and type I interferons are critical GC targets for regulating STAT1 activity and may account for overall GC effectiveness in inflammation suppression in the clinically relevant time frame.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21606371</pmid><doi>10.1073/pnas.1017296108</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological Sciences Blotting, Western Cell activation Cells, Cultured Cytokines Data processing Dexamethasone - pharmacology Effects Glucocorticoids Glucocorticoids - pharmacology Inflammation Interferon Interferon Regulatory Factor-3 - metabolism Interferon-alpha - metabolism Interferon-beta - pharmacology Interferons Interleukin-12 Subunit p40 - metabolism Interleukin-6 - metabolism Janus Kinase 2 - metabolism Ligands Lipopolysaccharides - pharmacology Macrophages Macrophages - cytology Macrophages - drug effects Macrophages - metabolism Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Phosphorylation Phosphorylation - drug effects Physiological regulation Poly I-C - pharmacology Pretreatment Receptors, Interferon - metabolism Secretion Signal transduction SOCS-1 protein Stat1 protein STAT1 Transcription Factor - genetics STAT1 Transcription Factor - metabolism Suppressor of Cytokine Signaling 1 Protein Suppressor of Cytokine Signaling Proteins - genetics Suppressor of Cytokine Signaling Proteins - metabolism T cell receptors TLR3 protein Toll-like receptors Toll-Like Receptors - metabolism transactivators Transcription |
| title | Glucocorticoids target suppressor of cytokine signaling 1 (SOCS1) and type 1 interferons to regulate Toll-like receptor-induced STAT1 activation |
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