Specific Modulation of Astrocyte Inflammation by Inhibition of Mixed Lineage Kinases with CEP-1347

Falsig, Jeppe; Pörzgen, Peter; Lotharius, Julie; Leist, Marcel

Specific Modulation of Astrocyte Inflammation by Inhibition of Mixed Lineage Kinases with CEP-1347

Dateien

Jeppe_JI04.pdfGröße: 554.64 KBDownloads: 244

Datum

2004

Autor:innen

Falsig, Jeppe

Pörzgen, Peter

Lotharius, Julie

Leist, Marcel

URI (zitierfähiger Link)

http://nbn-resolving.de/urn:nbn:de:bsz:352-opus-82597

Link zur Lizenz

Urheberrechtlich geschützt

Open Access-Veröffentlichung

Open Access Green

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

The Journal of Immunology. 2004, 173(4), pp. 2762-2770. ISSN 0022-1767. eISSN 1550-6606

Zusammenfassung

Inflammatory conversion of murine astrocytes correlates with the activation of various MAPK, and inhibition of terminal MAPKs like JNK or p38 dampens the inflammatory reaction. Mixed lineage kinases (MLKs), a family of MAPK kinase kinases, may therefore be involved in astrocyte inflammation. In this study, we explored the effect of the MLK inhibitors CEP-1347 and CEP-11004 on the activation of murine astrocytes by either TNF plus IL-1 or by a complete cytokine mix containing additional IFN-{gamma}. The compounds blocked NO-, PG-, and IL-6 release with a median inhibitory concentration of ~100 nM. This activity correlated with a block of the JNK and the p38 pathways activated in complete cytokine mix-treated astrocytes. Although CEP-1347 did not affect the activation of NF-{kappa}B, it blocked the expression of cyclooxygenase-2 and inducible NO synthase at the transcriptional level. Quantitative transcript profiling of 17 inflammation-linked genes revealed a specific modulation pattern of astrocyte activation by MLK inhibition, for instance, characterized by up-regulation of the anti-stress factors inhibitor of apoptosis protein-2 and activated transcription factor 4, no effect on manganese superoxide dismutase and caspase-11, and down-regulation of major inflammatory players like TNF, GM-CSF, urokinase-type plasminogen activator, and IL-6. In conclusion, MLK inhibitors like CEP-1347 are highly potent astrocyte immune modulators with a novel spectrum of activity.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Zitieren

ISO 690

FALSIG, Jeppe, Peter PÖRZGEN, Julie LOTHARIUS, Marcel LEIST, 2004. Specific Modulation of Astrocyte Inflammation by Inhibition of Mixed Lineage Kinases with CEP-1347. In: The Journal of Immunology. 2004, 173(4), pp. 2762-2770. ISSN 0022-1767. eISSN 1550-6606

BibTex

@article{Falsig2004Speci-8605,
  year={2004},
  title={Specific Modulation of Astrocyte Inflammation by Inhibition of Mixed Lineage Kinases with CEP-1347},
  number={4},
  volume={173},
  issn={0022-1767},
  journal={The Journal of Immunology},
  pages={2762--2770},
  author={Falsig, Jeppe and Pörzgen, Peter and Lotharius, Julie and Leist, Marcel}
}

RDF

<rdf:RDF
    xmlns:dcterms="http://purl.org/dc/terms/"
    xmlns:dc="http://purl.org/dc/elements/1.1/"
    xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
    xmlns:bibo="http://purl.org/ontology/bibo/"
    xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#"
    xmlns:foaf="http://xmlns.com/foaf/0.1/"
    xmlns:void="http://rdfs.org/ns/void#"
    xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > 
  <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/8605">
    <dc:creator>Lotharius, Julie</dc:creator>
    <dc:creator>Pörzgen, Peter</dc:creator>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/8605/1/Jeppe_JI04.pdf"/>
    <dcterms:abstract xml:lang="eng">Inflammatory conversion of murine astrocytes correlates with the activation of various MAPK, and inhibition of terminal MAPKs like JNK or p38 dampens the inflammatory reaction. Mixed lineage kinases (MLKs), a family of MAPK kinase kinases, may therefore be involved in astrocyte inflammation. In this study, we explored the effect of the MLK inhibitors CEP-1347 and CEP-11004 on the activation of murine astrocytes by either TNF plus IL-1 or by a complete cytokine mix containing additional IFN-{gamma}. The compounds blocked NO-, PG-, and IL-6 release with a median inhibitory concentration of ~100 nM. This activity correlated with a block of the JNK and the p38 pathways activated in complete cytokine mix-treated astrocytes. Although CEP-1347 did not affect the activation of NF-{kappa}B, it blocked the expression of cyclooxygenase-2 and inducible NO synthase at the transcriptional level. Quantitative transcript profiling of 17 inflammation-linked genes revealed a specific modulation pattern of astrocyte activation by MLK inhibition, for instance, characterized by up-regulation of the anti-stress factors inhibitor of apoptosis protein-2 and activated transcription factor 4, no effect on manganese superoxide dismutase and caspase-11, and down-regulation of major inflammatory players like TNF, GM-CSF, urokinase-type plasminogen activator, and IL-6. In conclusion, MLK inhibitors like CEP-1347 are highly potent astrocyte immune modulators with a novel spectrum of activity.</dcterms:abstract>
    <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:format>application/pdf</dc:format>
    <dc:language>eng</dc:language>
    <dc:contributor>Pörzgen, Peter</dc:contributor>
    <dcterms:bibliographicCitation>First publ. in: The Journal of Immunology ; 173 (2004), 5. - S. 2762-2770</dcterms:bibliographicCitation>
    <dc:rights>terms-of-use</dc:rights>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dcterms:issued>2004</dcterms:issued>
    <dcterms:title>Specific Modulation of Astrocyte Inflammation by Inhibition of Mixed Lineage Kinases with CEP-1347</dcterms:title>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/8605/1/Jeppe_JI04.pdf"/>
    <dc:contributor>Leist, Marcel</dc:contributor>
    <dc:creator>Falsig, Jeppe</dc:creator>
    <dc:contributor>Falsig, Jeppe</dc:contributor>
    <dc:creator>Leist, Marcel</dc:creator>
    <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/8605"/>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <dc:contributor>Lotharius, Julie</dc:contributor>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2011-03-24T17:45:02Z</dc:date>
  </rdf:Description>
</rdf:RDF>

Universitätsbibliographie

Nein