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

• Published in: The Journal of immunology (1950) Vol. 173; no. 4; pp. 2762 - 2770
• Main Authors: Falsig, Jeppe, Porzgen, Peter, Lotharius, Julie, Leist, Marcel
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.08.2004
• Subjects: Animals; Astrocytes - drug effects; Astrocytes - enzymology; Astrocytes - immunology; Blotting, Western; Carbazoles - pharmacology; Cells, Cultured; Cyclooxygenase 2; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Enzyme Activation - immunology; Enzyme Inhibitors - pharmacology; Gene Expression - drug effects; Immunoassay; In Situ Hybridization; Indoles - pharmacology; Inflammation - immunology; Interleukin-6 - metabolism; Isoenzymes - drug effects; Isoenzymes - metabolism; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; MAP Kinase Kinase Kinases - drug effects; MAP Kinase Kinase Kinases - immunology; Mice; Mitogen-Activated Protein Kinase Kinases - drug effects; Mitogen-Activated Protein Kinase Kinases - metabolism; NF-kappa B - drug effects; NF-kappa B - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase - drug effects; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Polymerase Chain Reaction; Prostaglandin-Endoperoxide Synthases - drug effects; Prostaglandin-Endoperoxide Synthases - metabolism; Prostaglandins - metabolism; Transcription, Genetic - drug effects
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.173.4.2762

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 approximately 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-kappaB, 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.