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Originally published In Press as doi:10.1074/jbc.M203201200 on June 5, 2002

J. Biol. Chem., Vol. 277, Issue 33, 30359-30367, August 16, 2002
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Cyclooxygenase-2 and Presenilin-1 Gene Expression Induced by Interleukin-1beta and Amyloid beta 42 Peptide Is Potentiated by Hypoxia in Primary Human Neural Cells*

Nicolas G. Bazan and Walter J. LukiwDagger

From the Neuroscience Center and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112-2272

Lipid messengers and amyloid beta (Abeta ) peptides generated by cyclooxygenase-2 (COX-2) and presenilin-1 (PS1) mediate pro-inflammatory signaling and neural degeneration in Alzheimer's disease (AD) brain. This study provides data showing that the COX-2 and PS1 genes each transcribe rare, highly labile RNA species that display early response gene behavior in human neural (HN) cells in primary culture, down-regulation during human neural development, and up-regulation in AD neocortex and hippocampal CA1. Together, interleukin-1beta and amyloid beta 42 peptide [IL-1beta +Abeta 42] synergistically activated COX-2 and PS1 gene expression preceded by increases in AP1-, STAT1alpha -, and in particular NF-kappa Bp50/p65- and HIF-1alpha -DNA binding. These events were markedly potentiated by hypoxia and blocked by the antioxidant alpha -phenyl-N-tert-butyl nitrone. Broad transcription profiling further indicated that hypoxia-induced, [IL-1beta +Abeta 42]-treated HN cells display robust induction of COX-2 and PS1 as well as a pro-inflammatory gene family that includes NF-kappa Bp50/p105, IL-1beta precursor, and cytosolic phospholipase A2 genes. These findings indicate a novel [IL-1beta +Abeta 42]-mediated, hypoxia-enhanced, free radical-triggered gene program that drives inflammatory gene signaling and suggest a mechanism by which hypoxia during aging contributes episodically to amyloidogenesis, inflammation, and AD pathophysiology.

* This work was supported by United States Public Health Service Grants AG18031 from the NIA, National Institutes of Health (NIH) (to W. J. L.) and NS23002 from the NINDS, NIH (to N. G. B.) and by the EENT Foundation of the State of Louisiana. Part of this research was presented in abstract form at the American Society for Neuroscience Annual Meeting, August 26-31, 2001, Buenos Aires, Argentina and at the Society for Neuroscience 31st Annual Meeting, November 10-15, 2001, San Diego, CA.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Neuroscience Center and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA 70112-2272. Tel.: 504-599-0842; Fax: 504-568-5801; E-mail: wlukiw@lsuhsc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.