MAPK and NF-κB Pathways Are Involved in Bisphenol A-Induced TNF-α and IL-6 Production in BV2 Microglial Cells

Abstract

Microglial activation has been reported to play an important role in neurodegenerative diseases by producing pro-inflammatory cytokines. Bisphenol A (BPA, 2,2-bis (4-hydroxyphenyl) propane), known as a ubiquitous endocrine-disrupting chemical, is reported to perform both mimic- and anti-estrogen properties; however, whether it affects cytokine production or immune response in central nervous system remains unclear. The present study was aimed to explore whether BPA was involved in inflammatory action and to investigate the potential mechanisms in microglial cells. BV2, the murine microglial cell line, was used in the present work as the cell model. BPA-associated morphologic changes, cytokine responses, and signaling events were examined using immunofluorescence analysis, real-time PCR, enzyme-linked immunosorbent assay, and western blot. Our results indicated that BPA increased BV2 cells activation and simultaneously elevated tumor necrosis factor-α and interleukin 6 expression, which could be partially reversed by estrogen receptor antagonist, ICI182780. In addition, the c-Jun N-terminal protein kinase (JNK) inhibitor (SP600125), rather than ERK1/2 blocker (PD98059), displayed anti-inflammatory properties on BPA-elicited cytokine responses. Moreover, the inflammatory transcription factor NF-κB was specifically activated by BPA as well. These results, taken together, suggested that BPA may have functional effects on the response of microglial cell activation via, in part, the estrogen receptor, JNK, ERK mitogen-activated protein kinase, and NF-κB signaling pathways with its subsequent influence on pro-inflammatory action.

Palmitate Induces an Anti-Inflammatory Response in Immortalized Microglial BV-2 and IMG Cell Lines that Decreases TNFα Levels in mHypoE-46 Hypothalamic Neurons in Co-Culture

“…There have been numerous studies that indicate that mRNA levels correlate well to protein in steady-state conditions, with a gene-specific lag in protein synthesis [57]. Of interest, when bisphenol A was added to the BV-2 cells, both IL-6 and TNFα mRNA expression were induced, with a corresponding increase in protein levels, as measured by ELISA [58]. Similarly, IMG cells demonstrated a concomitant increase in protein with mRNA induction upon exposure to LPS and IL-4 [28].…”

Hydroxysafflor yellow A attenuates the expression of inflammatory cytokines in acute soft tissue injury

“…Inflammatory mediators (e.g., TNF-α and IL-1β) can activate multiple intracellular signalling molecules, such as MAPK and NF-κB, and thus trigger the expression of related genes1819. During acute soft tissue injury, skeletal muscle endothelial cells, macrophages, and neutrophils secrete a variety of proinflammatory cytokines and proteases that take part in early inflammation through the NF-κB and MAPK pathways.…”

Prenatal exposure to bisphenol-A is associated with Toll-like receptor–induced cytokine suppression in neonates

“…Results from recent studies have suggested the potential role of endocrine-disrupting chemicals such as BPA to modify immune cytokine response; however, most are results from indicated that the addition of BPA in macrophages significantly increased the production of TNF-α and IL-6 through NF-κB signaling pathways (20,21). In contrast, studies that implied inhibitory effect of BPA on cytokine production had experimental settings that pretreated immune cells with BPA followed by infection (bacteria or virus) or stimulation with lipopolysaccharide.…”

“…At present, we do not know whether the influence of BPA on TLR-triggered cytokine response is a result of direct effect of BPA on TLR expression or the result of an indirect effect of BPA that disrupted downstream signaling events. Nevertheless, several experimental studies have shown that BPA can alter cytokine production via the P13K/Akt, the MAPK/AP-1, or the NF-κB pathways, whereas no influence was observed on TLR4 surface expression (21,24,25). The observation from our study that IL-10 response to TLR ligands remained unperturbed by BPA concentration might also give indirect evidence that BPA had no direct effect on TLR expression, because theoretically, all cytokine production would have been altered if TLR expression, being the origin of the signaling pathway, was modified.…”

“…First, the fact that since immune system is composed of multiple cells and variable pathways, suppression of certain cytokines of the innate immune system may not have an overall effect in disease outcome. Second, several reports have shown cytokine production to respond to BPA in a dose-dependent manner (15,20,21,23). In some studies in which lower doses of BPA were used, no effect was seen on ex vivo immune cell function or disease progression in vivo (22,28,29).…”