Reactive gliosis (gliosis, glial activation) is a hallmark of disease-, trauma- and chemical-induced damage to the CNS. This response is characterized by activation of microglia and astrocytes at sites of damage. Despite the regional- and cell-type specific targets of individual nervous system insults, reactive gliosis represents a feature common to all types of neural injury. This implies that there are common ‘signals’ responsible for its induction, signals that remain to be elucidated. Discovery and characterization of the signaling events that lead to this common response to brain damage would enhance our ability to detect early signatures of the neurotoxic condition. To achieve this, we used various brain injury models [1-Methyl-4-phenyl-1, 2, 3, 6, -tetrahydropyridine (MPTP), methamphetamine (METH), kainic acid (KA), and traumatic brain injury (Stab)] as denervating tools to damage distinct areas of mouse brain and elicit a glial response. Applying genomic (cDNA microarray, real-time PCR) and proteomic (antibody microarray, Ciphergen ProteinChip platform, phosphoprotein immunoblots) analysis, we identifed the early induction of several ligands of the gp130 signal transducer family (IL-6, CNTF, LIF, OSM) and other cytokines and chemokines (TNF-á, MCP-1) known to activate the Janus kinase-signal transducer and activator of transcription (JAKSTAT) pathway. The temporal expression of these ligands and the specific activation of JAK2-STAT3 was selective to the target region and preceded the induction of GFAP and astrocyte hypertrophy across all brain injury models examined. Pharmacological inhibition of JAK2 with tyrphostin B42 (AG490) attenuated STAT3 activation and GFAP expression in the MPTP model. Taken together, our results suggest that the JAK2-STAT3 pathway is activated prior to induction of astrogliosis in multiple models of brain injury. Ligands and effectors associated with activation of this pathway may serve as early ‘biomarkers’ of neurological/neurotoxic hazards.
The Toxicologist. Society of Toxicology 44th Annual Meeting and ToxExpo, March 6-10, 2005, New Orleans, Louisiana