Differential involvement of TNFα in hypoxic suppression of astrocyte glutamate transporters

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Abstract
Transporter‐mediated glutamate uptake is a principal function of astrocytes. Our previous studies have shown that this process is compromised under hypoxic conditions through the NF‐κB mediated inhibition of expression of the glutamate transporters EAAT‐1 and EAAT‐2. Here, we demonstrate that identical conditions of hypoxia (1% O2, 24 h) lead to a dramatic increase in TNFα production from astrocytes without altering their viability. This hypoxia‐evoked production of TNFα was prevented in the presence of any of three mechanistically distinct NF‐κB inhibitors. Exogenous application of TNFα was without effect on EAAT‐1 expression as determined by Western blotting, but mimicked the effects of hypoxia to suppress expression of EAAT‐2. Furthermore thalidomide, which prevents TNFα production, was without effect on hypoxic suppression of EAAT‐1 but prevented hypoxic suppression of EAAT‐2. These data indicate that regulation of glutamate transporter expression in astrocytes by hypoxia is subtype specific. Regulation of both EAAT‐1 and EAAT‐2 is mediated by NF‐κB, and this transcriptional regulator is also required for increased production of TNFα. However, while TNFα is essential for hypoxic suppression of EAAT‐2, hypoxic modulation of EAAT‐1 expression is unaffected by this cytokine.