Divergent Effects of Arsenic on NF-κB Signaling in Different Cells or Tissues: A Systematic Review and Meta-Analysis

Abstract

Arsenic is ubiquitously present in human lives, including in the environment and organisms, and has divergent effects between different cells and tissues and between different exposure times and doses. These observed effects have been attributed to the nuclear transcription factor kappa B(NF-κB) signaling pathway. Herein, a meta-analysis was performed by independently searching databases including the Cochrane Library, PubMed, Springer, Embase, and China National Knowledge Infrastructure, to analyze effects of arsenic exposure on NF-κB signaling. Compared to controls, in the exposed group, p-IκB levels were found to be 8.13-fold higher (95% CI, 2.40-13.85; Z = 2.78; p = 0.005), IκB levels were 16.19-fold lower (95% CI, -27.44--4.94; Z = 2.78; p = 0.005), and NF-κBp65 levels were 0.77-fold higher (95% CI, 0.13-1.42; Z = 2.34; p = 0.02) for normal cells and tissue, while NF-κBp65 levels were 4.90-fold lower (95% CI, -8.49-1.31; Z = 2.62; p = 0.009), NF-κB activity was 2.45-fold lower (95% CI, -3.66-1.25; Z = 4.00; p < 0.0001), and DNA-binding activity of NF-κB was 9.75-fold lower (95% CI, -18.66-4.54; Z = 2.15; p = 0.03) for abnormal cells and tissue. Short exposure to high arsenic doses activated the NF-κB signaling pathway, while long exposure to low arsenic doses suppressed NF-κB signaling pathway activation. These findings may provide a theoretical basis for injurious and therapeutic mechanisms of divergent effects of arsenic.

Keywords: NF-κB; arsenic; meta-analysis.

Figure 1

Flowchart detailing the publication search strategy.

Figure 2

Effects of arsenic on phosphorylase inhibitor of kappa B (p-IκB). Forest plot showing the impact of arsenic treatment on p-IκB compared with controls. Abbreviations: SMD = standardized mean difference, IV = independent variable, 95% CI = 95% confidence interval.

Figure 3

Effects of arsenic on inhibitor of kappa B(IκB). Forest plot showing the impact of arsenic treatment on IκB compared with controls. Abbreviations: SMD = standardized mean difference, IV = independent variable, 95% CI = 95% confidence interval.

Figure 4

Effects of arsenic on nuclear transcription factor kappa B p65(NF-κBp65). Forest plot showing the impact of arsenic treatment on NF-κBp65 compared with controls. Abbreviations: SMD = standardized mean difference, IV = independent variable, 95% CI = 95% confidence interval.

Figure 5

Effects of arsenic on nuclear transcription factor kappa B(NF-κB). Forest plot showing the impact of arsenic treatment on NF-κB compared with controls. Abbreviations: SMD = standardized mean difference, IV = independent variable, 95% CI = 95% confidence interval.

Figure 6

Effects of arsenic on inhibitor of kappa B kinase(IKK). Forest plot showing the impact of arsenic treatment on IKK compared with controls. Abbreviations: SMD = standardized mean difference, IV = independent variable, 95% CI = 95% confidence interval.

Figure 7

Effects of arsenic on nuclear transcription factor kappa B activity(NF-κB activity). Forest plot showing the impact of arsenic treatment on NF-κB activity compared with controls. Abbreviations: SMD = standardized mean difference, IV = independent variable, 95% CI = 95% confidence interval.

Figure 8

Effects of arsenic on the DNA-binding activity of the nuclear transcription factor kappa B(DNA-binding activity of NF-κB). Forest plot showing the impact of arsenic treatment on the DNA-binding activity of NF-κB compared with controls. Abbreviations: SMD = standardized mean difference, IV = independent variable, 95% CI = 95% confidence interval.

Figure 9

Effects of arsenic on nuclear transcription factor kappa B mRNA(NF-κB mRNA). Forest plot showing the impact of arsenic treatment on NF-κB mRNA compared with controls. Abbreviations: SMD = standardized mean difference, IV = independent variable, 95% CI = 95% confidence interval.

Figure 10

Subgroup analyses to determine the effects of arsenic on NF-κB. Based on exposure timeanalysis, arsenic exposure times of ≤24 h promote phosphorylation of IκB(B1), induce weak NF-κB activity(B2), and increase NF-κBp65 expression (B3), while arsenic exposure times ˃24 h suppresses NF-κB activity(B2) and attenuates the DNA-binding activity of NF-κB(A3). Abbreviations: SMD = standardized mean difference. 1, 2, 3, and 4 represent the row number, A and B refer to the column number.

Figure 11

Subgroup analyses to determine the effects of arsenic on NF-κB. Based on exposure dose analysis, low doses of arsenic exposure were found to reduce IKK(A1), NF-κB activity (B2), and NF-κBp65 expression. Abbreviations: SMD = standardized mean difference. 1, 2, 3, and 4 represent the row number, A and B refer to the column number.

Figure 12

Funnel plot for NF-κB. The blue-dotted line shows the overall estimated standard mean difference. Evidence for publication bias was not found (p = 0.441). Abbreviations: SMD = standard mean difference, SE = standard error.

Figure 13

Sensitivity analysis for NF-κB. Stable results were observed for all studies, indicating that no individual study influenced the combined results. Abbreviations: CI = confidence interval.

Figure 14

The NF-κB signaling pathway. (A) shows that at high doses, the action of IKK enhances IκB phosphorylation, degrades IκB, reduces the content of IκB in the cytoplasm, and increases the DNA-binding activity of NF-κB in normal tissues or cells, thereby enhancing the expression of NF-κBp65 and NF-κB; (B) indicates that, in inflammatory or tumor cells, arsenic reduces cytoplasmic IKK levels, suppresses IκB phosphorylation, attenuates IκB degradation, increases cytoplasmic IκB levels, and weakens the DNA-binding activity of NF-κB, thereby decreasing the expression levels of NF-κB and NF-κBp65.