The immunomodulatory effects of lactoferrin and its derived peptides on NF-κB signaling pathway: A systematic review and meta-analysis

Abstract

Background: Lactoferrin is a versatile protein with important modulatory functions in inflammation and immune response. This glycoprotein can bind and sequester iron and LPS, thereby intervening in certain signaling pathways and biological processes. In the present meta-analysis, we aimed to pool experimental data regarding the immunomodulatory effects of lactoferrin and its derived peptides on the NF-κB signaling pathway.

Materials: We searched PubMed, Google Scholar, and Web of Science databases and obtained all related articles published before April 2022. Finally, 25 eligible studies were selected, and their reports were analyzed.

Methods: We used Review Manager Version 5.2 to compute the standardized mean difference (SMD) and its 95% confidence interval. In addition, the source of heterogeneity was explored using meta-regression and sensitivity analysis. The symmetry of the funnel plot and Egger's test were also used to evaluate publication bias utilizing Comprehensive Meta-Analysis Version 2.

Results: Comparing the group of cells and animals exposed to lipopolysaccharide alone with the group that received pretreatment with lactoferrin and its derivatives, we observed significant reductions in TNF-α, IL-1 beta, and IL-6 levels by 8.73 pg/mL, 2.21 pg/mL, and 3.24 pg/mL, respectively, in the second group. Additionally, IKK-β, p-IκB, and NF-κB (p65) levels were significantly lower by 7.37-fold, 15.02-fold, and 3.88-fold, respectively, in various cells and tissues.

Conclusion: Based on the results of this meta-analysis, lactoferrin and its derived peptides can be considered potent prophylactic and therapeutic candidates against inflammation-associated diseases by targeting the NF-kB pathway.

Keywords: NF-κB pathway; immunomodulatory; lactoferrin; meta-analysis.

Figure 1

Flowchart of the criteria for study selection.

Figure 2

Forest plot for the comparison of TNF‐α cytokine levels between the experimental group and control group. CI, confidence interval; IV, independent variable.

Figure 3

Forest plot for the comparison of IL‐1β cytokine levels between the experimental group and control group. CI, confidence interval; IV, independent variable.

Figure 4

Forest plot for the comparison of IL‐6 cytokine levels between the experimental group and control group. CI, confidence interval; IV, independent variable.

Figure 5

Forest plot for the comparison of IKK‐β levels between the experimental group and control group. CI, confidence interval; IV, independent variable.

Figure 6

Forest plot for the comparison of p‐IκBα levels between the experimental group and control group. CI, confidence interval; IV, independent variable.

Figure 7

Forest plot for the comparison of NF‐κB (p65) levels between the experimental group and control group. CI, confidence interval; IV, independent variable.

Figure 8

Funnel plot of the association between lactoferrin exposure and TNF‐α levels (A) and IL‐6 levels (B). No evidence of publication bias was found. SE, standard error; SMD, standard mean difference.

Figure 9

Inhibitory effects of lactoferrin on the upstream (IL‐6, TNF‐α, and IL‐1β cytokines) and downstream (IκBα, IKK‐β, and NF‐κB (p65) cytoplasmic) NF‐κB pathways.