Differential involvement of TNF alpha 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-kappaB 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 TNFalpha production from astrocytes without altering their viability. This hypoxia-evoked production of TNFalpha was prevented in the presence of any of three mechanistically distinct NF-kappaB inhibitors. Exogenous application of TNFalpha 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 TNFalpha 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-kappaB, and this transcriptional regulator is also required for increased production of TNFalpha. However, while TNFalpha is essential for hypoxic suppression of EAAT-2, hypoxic modulation of EAAT-1 expression is unaffected by this cytokine.
Boycott
Hannah E
HE
Division of Cardiovascular and Neuronal Remodelling, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, United Kingdom.
Wilkinson
Jenny A
JA
Boyle
John P
JP
Pearson
Hugh A
HA
Peers
Chris
C
D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism* / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D027322:Amino Acid Transport System X-AG; D014409:Tumor Necrosis Factor-alpha