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.

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.

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