Zinc and aluminum induce NF-kB-DNA binding and COX-2 gene expression in human neural progenitor cells in primary culture

VICENTE BERMÚDEZ; W.J. LUKIW; N.G. BAZAN

Buenos Aires

Congreso; Joint Meeting Eighteenth Biennal Meeting of the International Society for Neurochemistry (ISN) and Thirty-Second Annual Meeting of the American Society for Neurochemistry; 2001

International Society for Neurochemistry y American Society for Neurochemistry

The nuclear factor for kappaB (NF-kB) plays a key role in oxygen homeostasis and in the regulation of inflammatory gene transcription from inducible genes such as cyclooxygenase-2 (COX-2). In the present experiments the transition metal ion Zn2+ and the environmentally abundant neurotoxic cation Al3+ were tested for their ability to modulate NF-kB activation and COX-2 gene transcription in cultured normal human neural progenitor (NHNP) cells in primary culture. NHNP cells were grown to 50% confluence?after serum depletion to 10% for 24 h, cells were treated with 10 nM to 10 uM ZnCl2 and AICl3 for 3, 48 and 96 h. NF-kB-DNA binding was quantitated by gel shift assay at 0, 3, 48 and 96 h after metal incubation using a modified electrophoretic mobility gel-shift assay (Lukiw et al. 1999 JBC 274: 8630?38). RNA message abundance for the inducible COX-2 gene was determined using integrated RT-PCR. NF-kB-DNA binding was found to be markedly induced at least 2-fold by Zn2+ and at least 4-sold by Al3+ after 3 h of exposure. COX-2 RNA message was found to be induced 2- to 6-sold by both Zn2+ and Al3+ 3 h after incubation. The excessive generation of oxygen radicals and lipid peroxidation products appears to be a significant factor in neurodegeneration. Zn2+ and Al3+ have been implicated in the generation of free oxygen radicals. Aluminum salts and hydroxides are widely used as vaccine adjuvants to stimulate the immune response. Metal ion triggered immune and inflammatory cascades may play an important role in neural degeneration and provide new chelation targets for pharmacologic intervention. Supported by the EENT Foundation and NIH NS230002.