Lactoferrin is a multifunctional member of the transferrin family of nonheme iron-binding glycoproteins. Lactoferrin is found at the mucosal surface where it functions as a prominent component of the first line of host defense against infection and inflammation. The protein is also an abundant component of the specific granules of neutrophils and can be released into the serum upon neutrophil degranulation. While the iron-binding properties were originally believed to be solely responsible for the host defense properties ascribed to lactoferrin, it is now known that other mechanisms contribute to the broad spectrum anti-infective and anti-inflammatory roles of this protein. In this article, current information on the functions and mechanism of action of lactoferrin are reviewed, with particular emphasis on the activities that contribute to this protein's role in host defense. In addition, studies demonstrating that lactoferrin inhibits allergen-induced skin inflammation in both mice and humans, most likely secondary to TNF-alpha (tumor necrosis factor alpha) production, are summarized. Collectively, these results suggest that lactoferrin functions as a key component of mammalian host defense at the mucosal surface.

We previously reported the production of limited quantities of biologically active recombinant human lactoferrin in the filamentous fungus Aspergillus oryzae. In the present study, we report a modification of this production system combined with a classical strain improvement program that has enabled production of levels of recombinant human lactoferrin in excess of 2 g/l. The protein was expressed in Aspergillus awamori as a glucoamylase fusion polypeptide which was secreted into the growth medium and processed to mature human lactoferrin by an endogenous KEX-2 peptidase. The recombinant protein retains full biological activity in terms of its ability to bind iron and human enterocyte receptors. Furthermore, the recombinant protein functions as a potent broad spectrum antimicrobial protein.

Lactoferrin (LF) is a member of the transferrin family that is expressed and secreted by glandular epithelial cells and is found in the secondary granules of neutrophils. Originally viewed as an iron-binding protein in milk, with bacteriostatic properties, it is becoming increasingly evident that LF is a multifunctional protein to which several physiological roles have been attributed. These include regulation of iron homeostasis, host defense against a broad range of microbial infections, anti-inflammatory activity, regulation of cellular growth and differentiation and protection against cancer development and metastasis. While iron binding is likely central to some of the biological roles of LF, other activities, including specific interactions with mammalian receptors and microbial components, also contribute to the pleoitropic functional nature of this protein. In this article, recent advances in the understanding of these functions at the cellular and molecular level are discussed.

The transferrin family of non-heme iron binding glycoproteins are believed to play a central role in iron metabolism and have been implicated in iron transport, cellular iron delivery and control of the level of free iron in external secretions. Lactoferrin (LF) is a member of this family that is widely localized in external fluids including milk and mucosal secretions, in addition to being a prominent component of the secondary granules of neutrophils. Although structurally related to transferrin, LF appears to have a broader functional role mediated by both iron dependent and iron independent mechanisms. In this review, we will focus on our current understanding on the role of LF in regulating iron homeostasis and its role in host protection against microbial infection at the mucosal surface. In addition, recent insights obtained from analyzing the phenotypic consequences of LF ablation in lactoferrin knockout mice (LFKO), which challenge the long held dogma that LF is required for intestinal iron absorption in the neonate, are summarized.

SUMMARYLactoferrin (LF) is a member of the transferrin family of iron-binding glycoproteins to which several anti-in¯ammatory functions have been ascribed. LF has been shown to down-regulate expression of the pro-in¯ammatory cytokine tumour necrosis factor-a (TNF-a), although the possibility has been raised that the activity of LF in this regard was indirect and secondary to its ability to bind to and inactivate the bacterial lipopolysaccharide (LPS) used to induce cytokine production. However, the identi®cation of putative membrane receptors for LF raises the possibility that the interaction of LF with its receptor may be one important route through which this protein exerts anti-in¯ammatory activity. In the present investigations the biological properties of LF have been examined in a model of cutaneous immune function where the allergen-induced migration of epidermal Langerhans cells (LC) from the skin and their subsequent accumulation as dendritic cells (DC) in skin-draining lymph nodes are known to be dependent upon the de novo synthesis of TNFa, but independent of exogenous LPS. Consistent with the protein having direct anti-in¯ammatory properties, it was found that the intradermal injection of recombinant murine LF (either ironsaturated or iron-depleted LF) inhibited signi®cantly allergen (oxazolone) -induced LC migration and DC accumulation. That these inhibitory effects were secondary to the inhibition of local TNF-a synthesis was suggested by the ®ndings that ®rst, LF was unable to inhibit LC migration induced by intradermal injection of TNF-a itself, and second, that migration stimulated by local administration of another epidermal cytokine, interleukin 1b, which is also dependent upon TNF-a production, was impaired signi®cantly by prior treatment with LF. Finally, immunohistochemical analyses demonstrated the presence of LF in skin, associated primarily with keratinocytes. Collectively these data support the possession by LF of direct immunomodulatory and/or anti-in¯ammatory activity, probably associated in this case with inhibition of cytokine production. Furthermore, the results suggest that as a constituent of normal skin, LF may play a role in homeostatic regulation of cutaneous immune function.