Upregulation of gp130 and STAT3 activation in the rat hippocampus following transient forebrain ischemia

Abstract

To determine whether the pathophysiological processes after transient forebrain ischemia are mediated via a signal pathway involving gp130 (a signal transducer for the interleukin-6 family), we analyzed changes in the expression of gp130 and its downstream transcription factor, signal transducer and activator of transcription factor 3 (STAT3), in the rat hippocampus of a four-vessel occlusive ischemia model. Expression of gp130 mRNA was restricted to neurons of the pyramidal cell and granule cell layers in control animals. Four hours after ischemic injury, astrocytes expressed gp130 mRNA. Expression of gp130 increased preferentially in the CA1 and dentate hilar regions, and was maintained for at least 2 weeks. Increase in gp130 expression was accompanied by the activation of STAT3 following ischemic injury. Four hours after injury, STAT3 and phosphorylated STAT3 (pSTAT3) were observed in the nuclei of the dentate hilar region, and sequentially in the CA1 region at day 1. By day 3, STAT3 immunoreactivity markedly increased in these areas, where small cells with the morphology of astrocytes showed nuclear and cytoplasmic STAT3 and nuclear pSTAT3 immunoreactivities. These patterns were especially maintained in the CA1 area until 14 days of reperfusion. Double-labeling experiments revealed that the cells expressing STAT3 and pSTAT3 were glial fibrillary acidic protein-expressing reactive astrocytes. These results show a coordinated and long-lasting upregulation of gp130 mRNA and STAT3 activation in reactive astrocytes of the postischemic hippocampus, indicating that they may be involved in the astrocytic response to an ischemic insult.

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

“…Activation of STAT3 has been reported following excitotoxic injury (12), ischemia (10,11,13,45), cortical lesions (14), and nerve lesions (46), as well as following peripheral challenge with bacterial lipopolysaccharide (47). However, there is considerable variation in these reports with respect to the localization of activated STAT3.…”

“…These include JNK, ERK, and JAK/STAT pathways as downstream effectors potentially relevant to reactive gliosis. Unfortunately, trauma and ischemia activates these pathways in neurons as well as astrocytes (10,11). This is not surprising because these injury models damage a number of different cell types, including astroglia as well as neurons (12)(13)(14); therefore, induction and maintenance of astrogliosis may be influenced by a variety of factors emanating from multiple neural cell types.…”

Activation of Cytokine Signaling through Leukemia Inhibitory Factor Receptor (LIFR)/gp130 Attenuates Ischemic Brain Injury in Rats

“…Second, this region corresponds to the ischemic penumbra that can be salvaged by pharmacological agents (Memezawa et al, 1992). Leukemia inhibitory factor receptor and gp130 have been shown to be located in the cerebral and cerebellar neurons in normal rat brain (Watanabe et al, 1996;Yamakuni et al, 1996;Morikawa et al, 2000), although the alterations in these receptor components under pathological conditions was varied by investigators (Haas et al, 1999;Getchell et al, 2002;Choi et al, 2003). Getchell et al (2002) reported upregulation of LIFR mRNA in the olfactory receptor neurons after olfactory bulb ablation.…”

“…The survival and differentiation of astrocytes and oligodendroglia have been shown to be potentiated by LIFR/gp130 signaling, and astrocyte differentiation is dramatically impaired in either gp130-or LIFR-deficient mice (Nakashima et al, 1999;Butzkueven et al, 2002). In fact, activation of the JAK-STAT pathway involving Stat3 was observed in reactive astrocytes after cerebral ischemia (Choi et al, 2003;Justicia et al, 2000), and we have showed expression of endogenous LIF in astrocytes at 96 h of reperfusion after transient MCAO (Suzuki et al, 2000). Taken together, we think that an experimental protocol with a longer period after cerebral ischemia will be necessary to determine the exact role of signaling through LIFR/gp130 in glial cells.…”

Ambivalent Aspects of Interleukin-6 in Cerebral Ischemia: Inflammatory versus Neurotrophic Aspects

“…Other investigators have reported that reactive astrocytes express gp130 and CNTFR after ischemic insults, but not IL-6R (Choi et al, 2003;Kim et al, 2004;Vollenweider et al, 2003). Microglia, oligodendrocytes, and endothelial cells appear to express only gp130 (Park et al, 2000;Choi et al, 2003;Vollenweider et al, 2003;Kim et al, 2004;Suzuki et al, 2005). It is well known that glial cell cultures respond to IL-6 treatment.…”