Lead induces COX-2 expression in glial cells in a NFAT-dependent, AP-1/NFκB-independent manner

Abstract

Epidemiologic studies have provided solid evidence for the neurotoxic effect of lead for decades of years. In view of the fact that children are more vulnerable to the neurotoxicity of lead, lead exposure has been an urgent public health concern for decades of years. The modes of action of lead neurotoxic effects include disturbance of neurotransmitter storage and release, damage of mitochondria, as well as induction of apoptosis in cerebrovascular endothelial cells, astroglia and oligodendroglia. Our studies here, from a novel point of view, demonstrates that lead specifically caused induction of COX-2, a well known inflammatory mediator in neurons and glia cells. Furthermore, we revealed that COX-2 was induced by lead in a transcription-dependent manner, which relayed on transcription factor NFAT, rather than AP-1 and NFκB, in glial cells. Considering the important functions of COX-2 in mediation of inflammation reaction and oxidative stress, our studies here provide a mechanistic insight into the understanding of lead-associated inflammatory neurotoxicity effect via activation of pro-inflammatory NFAT3/COX-2 axis.

Effect of Lead (Pb) on Inflammatory Processes in the Brain

“…In the peripheral tissues, COX-1 is a constitutive form of cyclooxygenase, while COX-2 is an inducible form [49]. In contrast, COX-2 is the basic form expressed in neurons [50,51,52].…”

“…In pathological conditions, such as hypoxia/ischemia and seizures, as well as neurodegenerative diseases including Alzheimer’s disease (AD), it has been demonstrated that over expression of COX-2 is associated with neurotoxicity [54]. Wei et al [49] investigated the effect of various doses of Pb (from 25 to 100 μM) on the induction of COX-2 in rat C6 glioma cells, mouse BV2 microglia, in primary cultures of cortex neurons, in neural stem cells (NSCs) and RBE4 cells (brain endothelium). The results of that research showed that Pb causes an induction of COX-2 in C6, BV2, primary culture of cortical neurons and NSCs [45].…”

“…The results of that research showed that Pb causes an induction of COX-2 in C6, BV2, primary culture of cortical neurons and NSCs [45]. In RBE4 cells, Pb (at doses greater than 50 μM) caused only a slight increase in COX-2 gene expression [49]. …”

“…Wei et al [49] investigated the influence of Pb on the induction of COX-2 gene transcription in a mechanism mediated by transcription factors NF-κB, AP-1 and NFAT. In that study, only the NFAT transcription factor was up-regulated by exposure to Pb [49].…”

“…Wei et al [49] investigated the influence of Pb on the induction of COX-2 gene transcription in a mechanism mediated by transcription factors NF-κB, AP-1 and NFAT. In that study, only the NFAT transcription factor was up-regulated by exposure to Pb [49]. In order to confirm the critical role of transcription factor NFAT in the induction of gene transcription of COX-2 by Pb, the authors mutated NFAT binding sites within the promoter of the COX-2 gene, which resulted in the abolition of COX-2 gene transcription, thus confirming that NFAT plays a key role in the transcription of the COX-2 gene induced by Pb in glial cells.…”