Modulation of cytokine expression in human macrophages by endocrine-disrupting chemical Bisphenol-A

https://doi.org/10.1016/j.bbrc.2014.08.031Get rights and content

Highlights

  • Effects of BPA on the cytokines expression of human macrophages were investigated.

  • BPA increased pro-inflammation cytokines TNF-α and IL-6 production.

  • BPA decreased anti-inflammation IL-10 and TGF-β production.

  • ERα/β/ERK/NF-κB signaling involved in BPA-mediated cytokines expression.

Abstract

Exposure to environmental endocrine-disrupting chemical Bisphenol-A (BPA) is often associated with dysregulated immune homeostasis, but the mechanisms remain unclear. In the present study, the effects of BPA on the cytokines responses of human macrophages were investigated. Treatment with BPA increased pro-inflammation cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production, but decreased anti-inflammation cytokines interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) production in THP1 macrophages, as well as in primary human macrophages. BPA effected cytokines expression through estrogen receptor α/β (ERα/β)-dependent mechanism with the evidence of ERα/β antagonist reversed the expression of cytokines. We also identified that activation of extracellular regulated protein kinases (ERK)/nuclear factor κB (NF-κB) signal cascade marked the effects of BPA on cytokines expression. Our results indicated that BPA effected inflammatory responses of macrophages via modulating of cytokines expression, and provided a new insight into the link between exposure to BPA and human health.

Introduction

Endocrine disrupting chemicals (EDCs) are natural or synthetic compounds that have the ability within the body to alter endocrine functions often through mimicking or blocking endogenous hormones [1]. BPA, a common environmental endocrine disruptor, is widely used as a xenoestrogen product of epoxy resins, polycarbonate plastics, and flame retardants [2]. Recently, many studies showed that BPA can bioaccumulate in bodies of humans, and it has been detected in the urine of almost all adults and children, fetal serum during pregnancy, breast milk, follicular and amniotic fluid, human fetal livers, placental tissue, as well as blood serum [3], [4], [5], [6]. BPA can directly bind to estrogen receptors and has estrogenic effects. Although BPA has a lower affinity for nuclear estrogen receptors relative to 17-beta estradiol (E2), its estrogenic potency is equal to E2 for responses mediated by non-nuclear estrogen receptors [7]. Furthermore, BPA can also act as an antiestrogen, blocking the estrogenic response by competing with endogenous E2 [8]. Therefore, because of its reported endocrine-disruptor activity, BPA widespread exposure and creating the concern that long-lasting adverse health effects may arise as a potentially consequence [9].

In recent years, some reports have been concern about a potential link between exposure to BPA and the occurrence of human diseases. For example, early exposure to BPA showed a linked with developmental and reproductive abnormalities in both sexes, including fertility, male sexual function, sperm quality, sex hormone concentrations, endometrial disorders, and polycystic ovary syndrome [10], [11]. Accumulated studies also have revealed that BPA exposure may cause increased susceptibility to tumorigenesis and metabolic disease (i.e., type-2 diabetes, cardiovascular disease, liver function, and obesity) [12]. Among these health issues, increasing concern has been focused on the risk of BPA to immune function. General measures of immune function were shown to be negatively associated with BPA exposure [13]. Using animal model, many cell subsets of the murine immune system undergo extensive proliferation under BPA exposure [14].

Macrophages play a significant part in immunity and immune responses. These cells reside in every tissue of the body and their activations are the initial steps of inflammation [15]. Activation of macrophages secret inflammatory cytokines such as TNF-α that promotes an inflammatory response [16]. In this study, we investigated the effects of BPA on the generation of several regulatory cytokines in macrophage, as these cytokines are important in pro- and anti-inflammatory processes, respectively. The results herein provided evidence supporting the influence of BPA on the function of human macrophages, involving in activation of ERα/β/ERK/NF-κB signaling, with subsequent increased the expression of pro-inflammatory cytokines (TNF-α and IL-6), and decreased the expression of anti-inflammatory cytokines (TGF-β and IL-10) in human macrophages.

Section snippets

Reagents

BPA, phorbol-12-myristate-13 acetate (PMA), G-1, G15, and Human AB Serum were purchased from Sigma–Aldrich (St. Louis, MO, USA). RPMI 1640 medium and fetal bovine serum (FBS) were purchased from GIBCO BRL (Grand Island, NY, USA). PDTC, U0126, and ICI182,780 were obtained from Beyotime Institute of Biotechnology (Beyotime, Jiangsu, China). Primary antibodies against p-AKT (Ser473), p-p38MAPK (Thr180/Tyr182), p-ERK (Thr202/204), p-JAK2 (Tyr1007/1008), p-STAT1 (Tyr701), p-STAT3 (Tyr705), p-IκB

Effects of BPA on the expression of cytokines in THP1 macrophages

THP-1 is a human monocytic leukemia cell line. After treatment with phorbol esters, THP-1 cells differentiate into macrophage-like cells which mimic native monocyte-derived macrophages in several respects [19], as macrophage specific marker CD68 showed a significant increased in phorbol esters PMA (320 nM) treatment THP1 cells (Fig. S1A and B).

To examine the potential effects of BPA on the function of macrophages, we first assessed the effects of BPA on cell proliferation of THP-1 macrophages.

Discussion

Macrophages have been recognized as a critical effectors and regulators of inflammation and the innate immune response, and macrophages exert their regulatory functions, in part, through the release of cytokines. In the present study, we investigated the possible stimulative effects of BPA on human macrophages. The results demonstrated that BPA could increase cytokines TNF-α, IL-6 secretion, and inhibit cytokines TGF-β, IL-10 secretion. In addition, we found that BPA targets and regulates

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

This research was supported by the National Natural Science Foundation of China (Grant No. 31101071) and Guangdong Provincial Innovative Development of Marine Economy Regional Demonstration Projects (GD2012-D01-002).

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