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.
Highlights
Iron, an essential element for cell growth and proliferation, is a component of fundamental processes such as DNA replication and energy production
Tf-bound iron is released as ferrous ion, which is translocated via divalent metal transporter 1 (DMT1) into cytoplasm where it is sequestered by ferritin (Ftn)
anemia of inflammation (AI), the most severe iron homeostasis disorder, is difficult to prevent and cure because it is associated with high levels of IL-6, which in turn induce the deregulation of the main proteins involved in iron homeostasis: hepcidin, Fpn, Tf, TfRs, Cp and Heph [26]
Summary
An essential element for cell growth and proliferation, is a component of fundamental processes such as DNA replication and energy production. AI, the most severe iron homeostasis disorder, is difficult to prevent and cure because it is associated with high levels of IL-6, which in turn induce the deregulation of the main proteins involved in iron homeostasis: hepcidin, Fpn, Tf, TfRs, Cp and Heph [26]. Intracellular iron retention could be an inducer of the growth of facultative and obligate intracellular pathogens inside epithelial cells and macrophages, increasing infection severity [29,30] In this respect, the recent discovery of the tight correlation between iron and inflammatory homeostasis must take into account that infectious processes by intracellular bacteria are favored and enhanced by intracellular iron overload, making imperative a strong revision of the classical iron therapy. It is of utmost importance to counteract the persistence of the inflammatory status to rebalance iron levels between tissues/secretions and blood, avoiding intracellular iron accumulation and the increased infection severity
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