Differential Production of Interleukin-6 in the Brain and Spleen of Mice Treated With Lipopolysaccharide in the Presence and Absence of Lead

Abstract

The heavy metal lead (Pb) markedly augments the lethality of endotoxin in laboratory animals. Much of the tissue injury produced by endotoxin is thought to be mediated by cytokines. Thus, the effects of Pb on the regulation of interleukin-6 (IL-6), a proinflammatory cytokine that shows high correlation with symptoms of endotoxic shock, and the levels of corticosterone, a hormone produced to prepare the body to cope with stress, upon lipopolysaccharide (LPS; endotoxin) administration were investigated. After intravenous administration of LPS, the kinetics of IL-6 gene expression by Northern blot analysis revealed a rapid increase of IL-6 mRNA, which peaked by 2 h in the spleens and 3 h in the brains of B6C3F1 female mice, with or without Pb exposure. Peak production of IL-6 protein after LPS challenge was observed at 2 h in the spleens and 3 h in the sera regardless of Pb-treatment. However, Pb-exposed mice showed an altered kinetic profile of IL-6 appearance in the brain, in that the levels of IL-6 in the brains peaked at 4 h rather than 3 h, the peak for the control mice. Moreover, at two time points, the amounts of IL-6 were found to be higher in the brains of Pb-treated mice. Increases in IL-6 were detected in multiple areas of the brain, but Pb did not significantly enhance this level in any area. The observation of both IL-6 transcripts and protein in the brains of mice upon peripheral LPS administration is indicative of local de novo synthesis of IL-6 in the brain. IL-6 production in the brain may contribute to the centrally mediated effects of IL-6, since IL-6 in the brain is known to activate the hypothalamus-pituitary-adrenal (HPA) axis. Upon LPS challenge, corticosterone levels peaked at the 2-h time point and stayed elevated for 6 h regardless of Pb exposure. The increases in brain IL-6 and its extended expression by Pb do not appear to have significantly altered the HPA axis on the basis of the corticosterone level, but brain IL-6 is known to affect multiple brain functions such as long-term potentiation.

Lead (Pb) Exposure Enhances Expression of Factors Associated with Inflammation

“…Kishikawa et al (1998) had previously shown that Pb exposure increases mRNA and IL-6 protein levels in the brains of adult mice treated with lipopolysaccharide (LPS) [ 35 ].…”

COVID-19, an opportunity to reevaluate the correlation between long-term effects of anthropogenic pollutants on viral epidemic/pandemic events and prevalence

“…Early-life exposure to environmental and anthropogenic chemicals may result in reprogramming of the immune system. Exposure of the developing immune system to heavy metals, specifically lead, has been shown to adversely affect the generation of innate immune cells, such as macrophages and DCs (Fenga et al, 2017;Gao et al, 2007;Kishikawa and Lawrence, 1998). Dysregulated macrophages and DCs effector functions reduce phagocytosis, lysosomal activation, produce excessively reactive oxygen species, and other inflammatory mediators (i.e., TNF-α, PGE 2 ) by activation of the Erk/MAP kinase pathway, contributing thus to persistent Th2-biased immune responses and increasing the risk for inflammatory disorders and disease unmasked later in life (Kim and Lawrence, 2000).…”