Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo?
Autor: | Diane B. Miller, Stanley A. Benkovic, James P. O'Callaghan, Krishnan Sriram, Meleik A. Hebert |
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Rok vydání: | 2004 |
Předmět: |
Male
Nomifensine Time Factors Dopamine Dopamine Agents Ligands Biochemistry Leukemia Inhibitory Factor Stat3 Signaling Pathway Mice Dopamine Uptake Inhibitors Cytokine Receptor gp130 Protein phosphorylation Tissue Distribution Phosphorylation Chromatography High Pressure Liquid Mitogen-Activated Protein Kinase 1 Janus kinase 2 Membrane Glycoproteins Mitogen-Activated Protein Kinase 3 Glial fibrillary acidic protein biology Reverse Transcriptase Polymerase Chain Reaction Protein-Tyrosine Kinases Immunohistochemistry Astrogliosis Cell biology Up-Regulation DNA-Binding Proteins Protein Transport 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine Mitogen-Activated Protein Kinases Dimerization Signal Transduction STAT3 Transcription Factor DNA Complementary MAP Kinase Signaling System Immunoblotting Active Transport Cell Nucleus Enzyme-Linked Immunosorbent Assay Oncostatin M Models Biological Antigens CD Proto-Oncogene Proteins Glial Fibrillary Acidic Protein medicine Animals RNA Messenger Protein kinase A Molecular Biology Interleukin-6 Cell Biology Janus Kinase 2 medicine.disease Enzyme Activation Mice Inbred C57BL nervous system Gene Expression Regulation Astrocytes biology.protein Trans-Activators RNA Tyrosine Janus kinase Peptides |
Zdroj: | The Journal of biological chemistry. 279(19) |
ISSN: | 0021-9258 |
Popis: | Reactive gliosis is a hallmark of disease-, trauma-, and chemical-induced damage to the central nervous system. The signaling pathways associated with this response to neural injury remain to be elucidated, but recent evidence implicates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Here, we used the known dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to selectively damage striatal dopaminergic nerve terminals and elicit a glial response. We then analyzed changes in gene expression and protein phosphorylation, in vivo, to identify ligands and mediators of the JAK-STAT pathway that accompany glial activation. Administration of MPTP caused rapid tyrosine (Tyr-705) phosphorylation and nuclear translocation of STAT3 in striatal astrocytes, prior to the induction of glial fibrillary acidic protein mRNA and protein. Pharmacological protection of dopaminergic nerve terminals with nomifensine abolished MPTP-mediated phosphorylation and translocation of STAT3 and prevented induction of astrogliosis. Among the Janus kinase family of tyrosine kinases, only JAK2 was associated with the phosphorylation of STAT3 after MPTP and, inhibition of JAK2 by AG490, in vivo, attenuated both the phosphorylation of STAT3 and induction of GFAP. The p44/42 mitogen-activated protein kinase (MAPK; ERK1/2) also was activated by MPTP, but was not associated with activation of STAT3, because serine (Ser-727) was not phosphorylated. The mRNA for ligands of the gp130-JAK/STAT3 signaling pathway, interleukin-6, leukemia inhibitory factor, and oncostatin M were elevated prior to activation of STAT3 and induction of astrogliosis; neuroprotection with nomifensine blocked these effects of MPTP. Taken together, our results suggest that the gp130-mediated activation of JAK2/STAT3 signaling pathway may play a key role in the induction of astrogliosis. |
Databáze: | OpenAIRE |
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