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3071218 
Journal Article 
Hypoxia Potentiates LPS-Mediated Cytotoxicity of BV2 Microglial Cells In Vitro by Synergistic Effects on Glial Cytokine and Nitric Oxide System 
Frey, D; Jung, S; Brackmann, F; Richter-Kraus, M; Trollmann, R 
2015 
1 
Neuropediatrics
ISSN: 0174-304X
EISSN: 1439-1899 
46 
5 
321-328 
26356486 
WOS:000362124500004 
Background Microglial activation due to a variety of stimuli induces secretion of neurotoxic substances including inflammatory cytokines and nitric oxide (NO). Clinical studies indicate a cross-link between inflammatory and hypoxia-regulated pathways suggesting that bacterial infections markedly sensitize the immature brain to hypoxic injury. Methods The impact of inflammation and hypoxia on interleukin (IL)-1 beta, IL-6, tumor necrosis factor alpha (TNF-alpha), and NO secretion and microglia-induced cytotoxicity was investigated exposing BV2 cells to lipopolysaccharides (LPS) and hypoxia (1% O-2). Cytotoxicity, NO, and cytokine release was quantified by MTS and Griess assays and by enzyme-linked immunosorbent assays, respectively. Results LPS exposure of BV2 cells induced a significant, persistent production of NO, IL-1 beta, IL-6, and TNF-alpha. Even after LPS removal, ongoing NO and cytokine secretion was observed. Hypoxia mediated exclusively a significant, short-term IL-1 beta increase, but enhanced LPS-induced cytokine and NO secretion significantly. In addition, LPS-induced supernatants exhibited a stronger cytotoxic effect in glial and neuronal cells than LPS exposition (p < 0.001). Hypoxia potentiated LPS-induced cytotoxicity. Conclusion Present data prove that LPS-induced soluble factors rather than LPS exposure mediate microglial toxicity under conditions of hypoxia in vitro. Apart from potential protective effects of the hypoxia-inducible transcription factor (HIF)-1 alpha system, activation of proinflammatory pathways may markedly sensitize microglial cells to promote hypoxia-induced injuries of the developing brain. 
microglia; inflammation; cytokines; hypoxia; HIF-1 alpha; neurotoxicity