The Involvement of Lactoferrin in the Hyposideremia of Acute Inflammation

Abstract

The hyposideremia of inflammation was found to be based on a three-step mechanism involving lactoferrin, the iron-binding protein from the specific granules of neutrophilic leukocytes. (a) Lactoferrin is Released from Neutrophils in an Iron-Free Form. When phagocytosis was induced in neutrophils by zymosan or bacteria, lactoferrin was recovered in the incubation medium together with other constituents of the specific granules, such as alkaline phosphatase and lysozyme. Lactoferrin extracted from leukocytes was able to bind the amount of iron corresponding to its theoretical iron-binding capacity. After injection of endotoxin into rats, lactoferrin was detected in various tissues where it was normally absent, or in the plasma when the reticuloendothelial system (RES) had previously been blocked by injections of India ink or aggregated albumin. (b) Lactoferrin is Able to Remove the Iron from Transferrin. Significant exchange of iron from transferrin to lactoferrin was observed in vitro only at a pH below 7.0 or in the presence of a high concentration of citrate. However, the fast elimination of lactoferrin in vivo, when saturated with iron, might account for the observed transfer of iron to endogenous or administered apolactoferrin. Intravenous injection of human apolactoferrin into rats caused a marked decrease of the plasma iron level. The kinetics of this process, as well as controls with other proteins, ruled out the possibility of a secondary inflammatory effect due to phlogogenic contaminants. (c) Fe-Lactoferrin is Taken-up by the RES. By immunofluorescence, lactoferrin was shown to be bound and ingested by monocytes. The rate of elimination of human Fe-lactoferrin injected into rats was particularly fast when compared to that of human apolactoferrin, succinylated Fe-lactoferrin, or other human proteins. Blockade of the RES slowed down the rate of clearance of Fe-lactoferrin and was also found to retard the elimination of endogenous rat lactoferrin released by endotoxin. These experiments suggest the existence of specific receptors for Fe-lactoferrin on the membrane of macrophages.

The binding of human lactoferrin to mouse peritoneal cells.

“…The present work confirms and extends our previous observations that FeLf has a high affinity for the membrane of macrophages (18,19). Previous experiments had shown that human Lf which was injected into rats was quickly removed by the RES with a clearance rate dependent upon the iron content of the protein and its structural integrity.…”

Lactoferrin: a review

“…In such an environment iron exchange from transferrin is easier due to the lower pH suggesting that lactoferrin may contribute to local iron accumulation at sites of inflammation (Brock, 2002). Lactoferrin has long been known to be responsible for hypoferraemia through binding free iron and shuttling it back to macrophages (Van Snick et al, 1974).…”

Iron-binding proteins in sputum of chronic bronchitis patients with Haemophilus influenzae infections

“…Lactoferrin retains a high affinity for iron at pH values <4.5, unlike transferrin, which loses its affinity for iron at pH <5.0. At a low pH, lactoferrin may even obtain iron by exchange from transferrin [39]. Since in sputum the concentrations of lactoferrin are similar as those of transferrin (figs.…”