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J Neuroimmunol. 2001 Oct 1;119(2):365-76.

Inflammatory gene transcription in human astrocytes exposed to hypoxia: roles of the nuclear factor-kappaB and autocrine stimulation.

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Cellular Neurobiology Group, Institute for Biological Sciences, National Research Council of Canada, Montreal Road Campus, Bldg. M-54, K1A 0R6, Ottawa, ON, Canada.


Mechanisms of hypoxia-induced activation of nuclear factor-kappaB (NF-kappaB) and inflammatory genes were investigated in fetal human astrocytes in culture. Astrocytes were subjected to interleukin-1beta (IL-1beta; 50-100 u/ml; 4-24 h), or to a 4-h hypoxia (<2% O2) followed by a 4-24-h reoxygenation. NF-kappaB binding and transcriptional activity increased up to 10-fold in astrocytes exposed to IL-1beta, and up to 3-fold in astrocytes subjected to hypoxia followed by reoxygenation. Both IL-1beta- mRNAs and proteins hypoxia-induced NF-kappaB activation were blocked by the proteasome inhibitor, MG-132. MG-132 inhibited IL-1beta-induced up-regulation of IL-1beta and IL-8 mRNA and protein but increased hypoxia-stimulated expression/release of IL-1beta and IL-8. IL-1 receptor antagonist (IL-1Ra) blocked both hypoxic astrocyte-conditioned media-induced NF-kappaB activation and the expression/release of IL-1beta and IL-8. Astrocytes subjected to hypoxia in the presence of IL-1Ra failed to activate NF-kappaB, but expressed elevated levels of IL-1beta and IL-8. The data suggest that hypoxia/reoxygenation-induced up-regulation of IL-1beta and IL-8 in human astrocytes has two components, a NF-kappaB independent up-regulation during hypoxia, followed by amplification through autocrine IL-1beta-induced NF-kappaB activation during reoxygenation.

[Indexed for MEDLINE]

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