Effects of Tumor Necrosis Factor-alpha on the Expression of Inducible Nitric Oxide Synthase in Nerve Growth Factor-Responsive Pheochromocytoma Cells
M.S. Thomas, W.R. Zhang, A.C. Andorn, G. Taglialatela
University of Texas Medical Branch at Galveston,
301 University Blvd,
Galveston, Texas 77555
Inducible nitric oxide synthase (iNOS) has been reported in tangle-bearing neurons of patients with Alzheimer’s disease (AD), and can be induced by tumor necrosis factor-alpha (TNF-alpha). High CNS levels of TNF-alpha are associated with neurodegenerative diseases such as AD, where neurons dependent on neurotrophins such as nerve growth factor (NGF) are particularly affected. In this study we determined the effect of TNF-alpha on iNOS in NGF-responsive pheochromocytoma (PC12) cells. We found that while TNF-alpha and NGF alone were unable to induce iNOS, their simultaneous addition resulted in iNOS induction and the production of nitric oxide. Inhibiting the activation of nuclear factor-kappa B (NF-kappa B) with inhibitors such as SN50, pyrrolidinedithiocarbamate (PDTC), or an inhibitor of the 26S proteosome (PSI) blocked the NGF/TNF-alpha-promoted iNOS expression. Notably, it has also been shown that neuronal nitric oxide synthase (nNOS) may be selectively down regulated in AD CNS and our studies suggest that prolonged expression of iNOS (>72 hours) in PC12 cells results in a down regulation of constititively expressed nNOS. Moreover, in other models an inhibition of nNOS induces iNOS expression suggesting a regulatory role for nNOS in the increased cytokine/neurotrophin induced iNOS expression. Our results suggest that synergistic iNOS induction by TNF-alpha and NGF may occur in selective population of NGF-responsive neurons in the presence of elevated CNS levels of TNF-alpha, thus contributing to known age- or AD-associated impairments of such neuronal populations.
Key words:
oxidative stress, TNF-alpha, NGF, nitric oxide, aging
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