Abstract
Brain edema, due largely to astrocyte swelling, and the subsequent increase in intracranial pressure and brain herniation, are major complications of acute liver failure (ALF). Elevated level of brain ammonia has been strongly implicated in the development of astrocyte swelling associated with ALF. The means by which ammonia brings about astrocyte swelling, however, is incompletely understood. Recently, oxidative/nitrosative stress and associated signaling events, including activation of mitogen-activated protein kinases (MAPKs), as well as activation of the transcription factor, nuclear factor-kappaB (NF-κB), have been implicated in the mechanism of ammonia-induced astrocyte swelling. Since these signaling events are known to be regulated by the transcription factor, signal transducer and activator of transcription 3 (STAT3), we examined the state of STAT3 activation in ammonia-treated cultured astrocytes, and determined whether altered STAT3 activation and/or protein expression contribute to the ammonia-induced astrocyte swelling. STAT3 was found to be dephosphorylated (inactivated) at Tyrosine705 in ammonia-treated cultured astrocytes. Total STAT3 protein level was also reduced in ammonia-treated astrocytes. We also found a significant increase in protein tyrosine phosphatase receptor type-1 (PTPRT-1) protein expression in ammonia-treated cultured astrocytes, and that inhibition of PTPRT-1 enhanced the phosphorylation of STAT3 after ammonia treatment. Additionally, exposure of cultured astrocytes to inhibitors of protein tyrosine phosphatases diminished the ammonia-induced cell swelling, while cultured astrocytes over-expressing STAT3 showed a reduction in the astrocyte swelling induced by ammonia. Collectively, these studies strongly suggest that inactivation of STAT3 represents a critical event in the mechanism of the astrocyte swelling associated with acute liver failure.
Highlights
Brain edema, due largely to astrocyte swelling, and the subsequent increase in intracranial pressure and brain herniation, are major complications of acute liver failure (ALF)
We found no change in basal levels of phosphorylated and non-phosphorylated signal transducer and activator of transcription 3 (STAT3), as well as receptor-type protein tyrosine phosphatase (PTPRT) for up to five days
Astrocytes transfected with pExpress1-STAT3 increased total, as well as phosphorylated STAT3 protein expression, and such treatment was associated with a reduction in the ammonia-induced cell swelling, suggesting that deactivation of STAT3 represents a critical early event in the process leading to the astrocyte swelling in ALF
Summary
Due largely to astrocyte swelling, and the subsequent increase in intracranial pressure and brain herniation, are major complications of acute liver failure (ALF). Biology 2016, 5, 48 brain ammonia have been strongly implicated in the development of the astrocyte swelling (cytotoxic brain edema) associated with ALF [1,2,3]. Oxidative/nitrosative stress (ONS) and associated signaling events, including the activation of mitogen-activated protein kinases (MAPKs), as well as transcription factors p53, and nuclear factor-kappaB (NF-κB), have been implicated in the mechanism of ammonia-induced astrocyte swelling [4,5,6,7]. All of these signaling molecules are known to be regulated by the transcription factor, signal transducer and activator of transcription 3 (STAT3). Constitutive STAT3 activation is associated with various neoplasms that have anti-apoptotic and proliferative effects [8,9,10,11,12,13]
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