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Reactive gliosis is modulated by gp - 130 cytokines and microglial chemokines in ex - vivo brain slices.

Damiani-CL; Sriram-K; O'Callaghan-JP
Program No. 633.17. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2004 Oct; :1
Reactive gliosis is a hallmark of damage to the central nervous system (CNS). All CNS injuries result in glial activation which is characterized by the accumulation of glial fibrillary acidic protein (GFAP). Signaling pathways associated with this response remain elusive, but recent evidence implicates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. This pathway is a down-stream effector of cytokines linked to injury-induced astroglial activation, a cellular response that appears to require phosphorylation of ST A T3. For example, we demonstrated that administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in phosphorylation of STAT3 at Tyr-705, an effect that preceded the induction of GFAP, thereby implicating JAK-STAT in astrogliosis. Here, we used coronal slices of mouse striatum to identify mediators of JAK-ST AT that accompany glial activation. Striatal slices (350 microM thick) were made from C57BI/6 mice treated with MPTP (12.5mg/kg) or saline. At 12 hours post-treatment, p-STAT3 was present in slices from MPTP treated animals while absent in controls, recapitulating in vivo observations. Striatal slices then were incubated in oxygenated buffer. Within 45 minutes both MPTP treated and control striata expressed p-STAT3, indicating STAT3 activation can also result from slice injury. To clarify ligands that are responsible for STAT3 activation, slices were incubated with a gp-130 cytokine [leukemia inhibitory factor (LlF) or oncostatin M (OSM)] or a glial-derived chemokine (CCL-2/MCP-1) and then assayed for p-STAT3. Incubation of striata with LlF and OSM promoted glial activation as evidenced by increased p-STAT3 and GFAP protein whereas incubation with CCL-2 inhibited gliosis. The effects of CCL-2 were reversed after neutralization with alpha-CCL-2. These data suggest that pSTAT3 is an early event in glial activation and that both glial-derived chemokines and gp-130 cytokines modulate reactive. gliosis.
Central-nervous-system; Central-nervous-system-disorders; Cellular-reactions; Cellular-function; Cell-function; Cell-transformation; Laboratory-animals; Animal-studies; Animals; In-vivo-study
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Program No. 633.17. 2004 Abstract Viewer/Itinerary Planner