Lead activates nuclear transcription factor-kappaB, activator protein-1, and amino-terminal c-Jun kinase in pheochromocytoma cells.

Lead (Pb) is a ubiquitous environmental contaminant that produces variety of effects on the central and peripheral nervous system, induces inflammatory response, and modulates immune functions. Though increase in lipid peroxidation and reactive oxygen intermediates (ROI) have been observed in Pb-induced toxicity, the molecular mechanism underlying these effects is largely unknown. Since nuclear factor kappa B (NF-kappaB) and activator protein (AP-1) are known to be activated by oxidative stress, we hypothesized that Pb-induced effects may be modulated via these transcription factors. The effects of Pb on NF-kappaB, AP-1, and related kinases were studied in pheochromocytoma cells (PC-12). Our results showed that treatment of murine PC-12 cells with Pb resulted in activation of NF-kappaB and degradation of IkappaBalpha (the inhibitory subunit of NF-kappaB). Pb-induced NF-kappaB dependent gene expression was also enhanced. The binding of Pb-induced NF-kappaB to DNA was blocked by antibodies for p65 and p50 but not by c-Rel or nonspecific antibodies such as cyclin D-1 and preimmune serum, suggesting that NF-kappaB consisted of p65 and p50 subunits. Similar to its effects on NF-kappaB, Pb also activated AP-1 in a time- and dose-dependent manner. Besides activating these transcription factors, Pb was also found to upregulate the related kinases such as mitogen activated protein kinase kinase (MEK) and c-Jun N-terminal kinase (JNK) (also known as stress-activated protein kinase) in a dose- and time-dependent manner. Thus, these results suggest that NF-kappaB, AP-1, MEK, and JNK may be important mediators of Pb-induced signaling in gene expression mediating inflammatory response and immunomodulation. Copyright 1999 Academic Press.