title: Protective role of STAT3 in NMDA and glutamate-induced neuronal death: negative regulatory effect of SOCS3.
abstract: The present study investigates the involvement of the IL-6 family of cytokines, activation of the transcription factor Signal Transducer and Activator of Transcription-3 (STAT3), and the role of Suppressor Of Cytokine Signaling-3 (SOCS3) in regulating excitotoxic neuronal death in vitro. Biochemical evidence demonstrates that in primary cortical neurons and SH-SY5Y neuroblastoma cells, IL-6 cytokine family members, OSM and IL-6 plus the soluble IL-6R (IL-6/R), prevent NMDA and glutamate-induced neuronal toxicity. As well, OSM and IL-6/R induce tyrosine and serine phosphorylation of STAT3 in primary cortical neurons and SH-SY5Y cells. Studies using Pyridine 6 (P6), a pan-JAK inhibitor, demonstrate that the protective effect of OSM and IL-6/R on neuronal death is mediated by the JAK/STAT3 signaling pathway. In parallel to STAT3 phosphorylation, OSM and IL-6/R induce SOCS3 expression at the mRNA and protein level. P6 treatment inhibits SOCS3 expression, indicating that STAT3 is required for OSM and IL-6/R-induced SOCS3 expression. Lentiviral delivery of SOCS3, an inhibitor of STAT3 signaling, into primary neurons and SH-SY5Y cells inhibits OSM and IL-6/R-induced phosphorylation of STAT3, and also reverses the protective effect of OSM and IL-6/R on NMDA and glutamate-induced neurotoxicity in primary cortical neurons. In addition, treatment with IL-6 cytokines increases expression of the anti-apoptotic protein Bcl-xL and induces activation of the Akt signaling pathway, which are also negatively regulated by SOCS3 expression. Thus, IL-6/R and OSM-induced SOCS3 expression may be an important factor limiting the neuroprotective effects of activated STAT3 against NMDA and glutamate-induced neurotoxicity.
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Keun W
authors.initials: KW
authors.lastname: Park
authors.forename: Susan E
authors.initials: SE
authors.lastname: Nozell
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D015850:Interleukin-6; D018696:Neuroprotective Agents; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051020:bcl-X Protein; D018698:Glutamic Acid; D016202:N-Methylaspartate; D053612:Janus Kinases; D051057:Proto-Oncogene Proteins c-akt