INTRODUCTION: Pro-inflammatory cytokines are strongly involved in the pathogenesis of hepatic encephalopathy (HE) associated with both acute and chronic liver failure. Elevation of IL‑1, Il‑6 and especially TNF‑α in blood strictly correlates with severity of observed symptoms in HE patients. On the other hand also a significant relationship is observed between TNF‑ α and received the most attention -ammonia theory in the pathogenesis of HE. In astrocytes, excess of formed glutamine (Gln) as a product of ammonia detoxification is further metabolized by mitochondrial glutaminase (GLS), which is thought to play a central role in the generation of excitotoxic glutamate (Glu). So far reported data suggest that TNF‑α increased the expression of neuronal and microglial GLS. AIM(S): The aim of this study was to analyze the expression of gls1 in rat astrocytes subjected to two key pathogenic factors operating in HE: ammonia and pro‑inflammatory factors: TNF‑α, IL‑1, Il‑6. METHOD(S): In the following study we measured the gene expression and protein level of gls1 isoformes (KGA and GAC) in rat cortical astrocytes treated by 48 h with TNF‑α (50 ng/ml), 10n IL‑6 (10 ng/ml), IL‑1 (10 ng/ml) and/ or 5 mM ammonium chloride (ammonia). We also used inhibitors of nuclear factor kappa B – Bay‑11, STAT‑1 – flutarabine and STAT-3 (STA-21). RESULTS: TNF‑α specifically increased the expression of KGA, but not GAC, at both mRNA and protein level. Used interleukines nor ammonia did not affect gls1 expression. Observed phenomena were significantly abolished by STAT-3 inhibition. CONCLUSIONS: Our findings demonstrate that TNF‑α ‑induced up‑regulation of GLS in cultured astrocytes, which may contribute to the response to an inflammatory stimulus associated with HE. The response appears to be triggered at the level of transcription of the KGA isoform and may involve a signaling pathway associated with STAT3. Our findings underscore the potential role of inflammatory cytokines in the derangement of astrocytic Glu metabolism associated with HE. FINANCIAL SUPPORT: Supported by the National Science Centre (NCN) grant no. 2014/15/N/NZ5/03634.
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