Differential involvement of TNFα in hypoxic suppression of astrocyte glutamate transporters

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-kappa B mediated inhibition of expression of the glutamate transporters EAAT-1 and EAAT-2. Here, we demonstrate that identical conditions of hypoxia (1% O-2, 24 h) lead to a dramatic increase in TNF alpha production from astrocytes without altering their viability. This hypoxia-evoked production of TNF alpha was prevented in the presence of any of three mechanistically distinct NF-kappa B inhibitors. Exogenous application of TNF alpha 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 TNF alpha 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-kappa B, and this transcriptional regulator is also required for increased production of TNF alpha. However, while TNF alpha is essential for hypoxic suppression of EAAT-2, hypoxic modulation of EAAT-1 expression is unaffected by this cytokine. (C) 2008 Wiley-Liss, Inc.