JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia

Abstract

Increased levels of interleukin-6 (IL-6) play a role in post-ischemic cerebral inflammation. IL-6 binding to its receptors induces phosphorylation of the receptor associated janus kinases (JAKs), and the down-stream signal transducer and activator of transcription (STAT) family of transcription factors, which amplify the IL-6 signal transduction. We evaluated the functional significance of JAK2 and STAT3 activation in focal ischemia-induced neuronal damage. Transient middle cerebral artery occlusion in adult rats led to increased JAK2 and STAT3 phosphorylation in the ipsilateral cortex and striatum after 6-72 h of reperfusion. Fluorescent immunohistochemistry with cell specific markers (NeuN for neurons, glial fibrillary acidic protein for reactive astrocytes and ED1/OX42 for activated macrophages/microglia) showed that both pJAK2 and pSTAT3 staining is predominantly localized in the macrophages/microglia in the post-ischemic brain. Intracerebroventricular infusion of rats with AG490 (a JAK2 phosphorylation inhibitor) prevented the post-ischemic JAK2 and STAT3 phosphorylation and significantly decreased the infarct volume, number of apoptotic cells and neurological deficits, compared to vehicle control. Furthermore, intracerebral injection of siRNA specific for STAT3 led to curtailed STAT3 mRNA expression and phosphorylation, decreased infarct volume, fewer apoptotic cells and improved neurological function following transient middle cerebral artery occlusion. These studies show that JAK2-STAT3 activation plays a role in post-ischemic brain damage.

Long Noncoding RNA FosDT Promotes Ischemic Brain Injury by Interacting with REST-Associated Chromatin-Modifying Proteins

“…NFB2 gene encodes NFB2 p100/p52 protein, which exhibits IB properties due to a cluster of ankyrin repeats in the C-terminal domains. NFB2 p100 mediates cytoplasmic retention of NFB RelA/p65 to prevent its nuclear translocation, and thus minimizes inflammation and cell death after ischemia (Schneider et al, 1999;Zhang et al, 2005). Hence, RESTmediated repression of NFB2 might be a promoter of neuronal death after ischemia.…”

“…ously (Satriotomo et al, 2006;Pandi et al, 2013). In brief, siRNA mix (8 nmol in 6 l buffer ϩ 2 l invivofectamine) was incubated at room temperature for 15 min and injected with a Hamilton syringe (1 l/5 min) into cerebral cortex (bregma; Ϫ0.2 mm posterior, 3 mm dorsoventral, 4.5 mm lateral) (Paxinos and Watson, 1998).…”

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

“…A novel mechanism for the PPAR-gamma-independent anti-inflammatory actions of TZDs, is the involvement of the Janus kinase (JAK) and the STAT signaling pathways (33,67,68). Transphosphorylation of the cytokine receptor-associated JAK leads to its dimerization and phosphorylation of the downstream STATs.…”

“…SOCS acts as a negative feedback regulator and inhibits further JAK and STAT phosphorylation, thus preventing the upregulation and binding of cytokines to their receptors after an acute CNS insult (33,67). Our recent studies showed that focal ischemia induces a massive upregulation of IL-6, which increases the phosphorylation of the JAK2 and STAT3 isoforms in the ischemic hemisphere (68,69,123). Although physiological levels of STAT3 activation are essential for normal cellular functions, its excessive phosphorylation as seen after focal cerebral ischemia is neurotoxic.…”

“…Huang et al (28) demonstrated that IL-4 induces the generation of endogenous ligands for PPAR-gamma by activating the 12/15-lipoxygenase pathway in macrophages, suggesting an IL-4-mediated down-regulation of iNOS expression. These studies suggested that PPAR-gamma agonists might mediate anti-inflammatory effects through PPAR-gamma-independent mechanisms as well.A novel mechanism for the PPAR-gamma-independent anti-inflammatory actions of TZDs, is the involvement of the Janus kinase (JAK) and the STAT signaling pathways (33,67,68). Transphosphorylation of the cytokine receptor-associated JAK leads to its dimerization and phosphorylation of the downstream STATs.…”