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?
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.
Sriram
Krishnan
K
HELD/TMBB, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA.
Benkovic
Stanley A
SA
Hebert
Meleik A
MA
Miller
Diane B
DB
O'Callaghan
James P
JP
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D001253:Astrocytes / Q000378:metabolism* / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D050822:Cytokine Receptor gp130; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2; D053605:Leukemia Inhibitory Factor; D008024:Ligands; D020935:MAP Kinase Signaling System; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009627:Nomifensine / Q000494:pharmacology; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D015703:Antigens, CD; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D005904:Glial Fibrillary Acidic Protein; C494200:Il6st protein, mouse; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; C508352:Osm protein, mouse; D010455:Peptides; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D053683:Oncostatin M; D050822:Cytokine Receptor gp130; D009627:Nomifensine; D014443:Tyrosine; D012313:RNA; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D004298:Dopamine