NF-κB-An Important Player in Xenoestrogen Signaling in Immune Cells

Abstract

The proper functioning of the immune system is critical for an effective defense against pathogenic factors such as bacteria and viruses. All the cellular processes taking place in an organism are strictly regulated by an intracellular network of signaling pathways. In the case of immune cells, the NF-κB pathway is considered the key signaling pathway as it regulates the expression of more than 200 genes. The transcription factor NF-κB is sensitive to exogenous factors, such as xenoestrogens (XEs), which are compounds mimicking the action of endogenous estrogens and are widely distributed in the environment. Moreover, XE-induced modulation of signaling pathways may be crucial for the proper development of the immune system. In this review, we summarize the effects of XEs on the NF-κB signaling pathway. Based on our analysis, we constructed a model of XE-induced signaling in immune cells and found that in most cases XEs activate NF-κB. Our analysis indicated that the indirect impact of XEs on NF-κB in immune cells is related to the modulation of estrogen signaling and other pathways such as MAPK and JAK/STAT. We also summarize the role of these aspects of signaling in the development and further functioning of the immune system in this paper.

Keywords: NF-κB; endocrine disrupting chemicals; xenoestrogen signaling; xenoestrogens.

Figure 1

Xenoestrogens in human tissues. Xenoestrogens are absorbed into the human body via digestion, inhalation and transdermal absorption. Compounds were detected in human hairs, breast milk, blood, adipose tissue, cord blood, amniotic fluid, urine, menstrual blood, and semen [13,14,15,16,17,18,19].

Figure 2

Schematic overview of the ligand-dependent activation of ERs and its interaction with NF-κB pathway in immune cells. HSPs dissociate ERs and allow E2 to bind with them. Free ERs undergo conformational transformations that allow their dimerization. In the nucleus, ERs may bind EREs to interact with other transcription factors. Additionally, ERs suppress NF-κB pathway: ERs may directly bind NF-κB subunits or block NF-κB-binding sites on genes promoter. Abbreviations: E2—estradiol; ERα/β—estrogen receptor α/β; EREs—estrogen response elements; HSP—heap shock protein; NF-κB—nuclear factor κB [48,49,50].

Figure 3

Schematic overview of the canonical (classical) and non-canonical (alternative) NF-κB signaling pathways. Activation of the canonical cascade of NF-κB requires signal transmission via membrane receptors and activation of IKK complex containing NEMO. IKK phosphorylates IκB inhibitor, which is binding NF-κB dimers: p65 and p50. K48-linked polyubiquitination leads to proteasomal degradation of the phosho-IκB, whereas K63-linked polyubiquitin is responsible for stabilizing the membrane receptor signalosome, enable recruitment of downstream adaptors or complexes, and activating kinases. Released NF-κB dimers are translocated into the cell nucleus and regulate transcription of genes. Non-canonical NF-κB pathway is dependent on activation NIK and IKKα complex. The NF-κB dimers remain inactive until IKKα complex phosphorylates p100. Phosphorylation and K48-linked polyubiquitination of p100 cause its proteasome processing which leads to forming p52 subunit. RelB and p52 NF-κB dimers are translocated into the cell nucleus and act as a transcription factor. Abbreviations: BAFF—B-cell activating factor; CD40L—cluster of differentiation 40 ligand; IKK—IκB kinase; IL—interleukin; K48/K63—lysine 48/63; LPS—lipopolysaccharide; LTβ receptor—lymphotoxin β-receptor; NF-κB—nuclear factor κB; NIK—NF-κB-inducing kinase; P—phosphorylation; RANK—receptor activator of nuclear factor kappa-Β; RANKL—receptor activator of nuclear factor kappa-Β ligand; TAKTGF-β-activating kinase; TLR receptor—Toll-like receptor; TNFα/β—tumor necrosis factor α/β; Ub—ubiquitination [75,76,77,78,79,80,81].

Figure 4

Model of xenoestrogens-induced modulation of NF-κB signaling in immune cells. Xenoestrogens may, directly and indirectly, impact on elements of the NF-κB pathway. Direct effect includes impact on IκB phosphorylation and degradation, NF-κB expression and translocation from cytoplasm to nucleus, as well as a change in transcriptional activity. Xenoestrogens activate numerous intracellular pathway, e.g., ERK1/2 MAPK, JNK MAPK, p38 MAPK, JAK/STAT, PI3K/Akt, PKC as well as ERs signaling, which inhibit NF-κB activation, decrease expression of IκB and NF-κB dimers, and NF-κB promoter activities. Abbreviations: ERK1/2 MAPK—1/2 extracellular signal-regulated kinases pathway; ERα/β—estrogen receptor α/β; IKK—IκB kinase; JAK/STAT—Janus kinases/signal transducer and activator of transcription protein family pathway; JNK MAPK—c-Jun N-terminal kinases pathway; NF-κB—nuclear factor κB; P—phosphorylation; p38 MAPK—p38 mitogen-activated protein kinases pathway; PI3K/Akt—phosphatidylinositol 3-kinase/protein kinase B pathway; PKC—protein kinase C; Ub—ubiquitination; ↑—increase; ↓—decrease; ↑↓—increase or decrease; ?—not tested; (+)—activation [5,102,104,105,107,108,109,110,111,112,113,114,115,117,121].