Lactoferrin: A Natural Glycoprotein Involved in Iron and Inflammatory Homeostasis

Abstract

Human lactoferrin (hLf), an iron-binding multifunctional cationic glycoprotein secreted by exocrine glands and by neutrophils, is a key element of host defenses. HLf and bovine Lf (bLf), possessing high sequence homology and identical functions, inhibit bacterial growth and biofilm dependently from iron binding ability while, independently, bacterial adhesion to and the entry into cells. In infected/inflamed host cells, bLf exerts an anti-inflammatory activity against interleukin-6 (IL-6), thus up-regulating ferroportin (Fpn) and transferrin receptor 1 (TfR1) and down-regulating ferritin (Ftn), pivotal actors of iron and inflammatory homeostasis (IIH). Consequently, bLf inhibits intracellular iron overload, an unsafe condition enhancing in vivo susceptibility to infections, as well as anemia of inflammation (AI), re-establishing IIH. In pregnant women, affected by AI, bLf oral administration decreases IL-6 and increases hematological parameters. This surprising effect is unrelated to iron supplementation by bLf (80 μg instead of 1-2 mg/day), but to its role on IIH. AI is unrelated to the lack of iron, but to iron delocalization: cellular/tissue overload and blood deficiency. BLf cures AI by restoring iron from cells to blood through Fpn up-expression. Indeed, anti-inflammatory activity of oral and intravaginal bLf prevents preterm delivery. Promising bLf treatments can prevent/cure transitory inflammation/anemia/oral pathologies in athletes.

Keywords: anemia; athletes; cytokines; homeostasis; inflammation; iron; lactoferrin; oral care.

Figure 1

Structure of lactoferrin. The N-lobe on the left and the C-lobe on the right are divided into four domains, labeled N1, N2, C1, C2. The red spheres represent the two ferric ions in each iron-binding site.

Figure 2

Lactoferrin iron-binding site. Iron-binding site in the N-lobe: two tyrosine (Y92 and Y192), one aspartic acid (D60), one histidine (H253) and one carbonate anion together with the arginine residue (R121). Two basic residues behind the iron site, an arginine (R210) and a lysine (K301) help modulate iron release.

Figure 3

(A) Structure of lactoferrin in apo-form (iron-free); and (B) structure of lactoferrin in holo-form (iron-saturated).

Figure 4

The bacterial iron transport mechanisms: (i) synthesis of high affinity ferric ion chelators, siderophores; (ii) receptor mediated endocytosis of the main iron-binding molecules (lactoferrin, transferrin, hemopexin, haptoglobin, hemoglobin and heme); (iii) passive transport mediated by bacterial reductase.

Figure 5

Lactoferricin localization in bovine lactoferrin. The dotted section indicates the bovine lactoferricin.