Regulation of epidermal Langerhans cell migration by lactoferrin

Lactoferrin (LF) is a member of the transferrin family of iron-binding glyc oproteins to which several anti-inflammatory functions have been ascribed. LF has been shown to down-regulate expression of the pro-inflammatory cytok ine tumour necrosis factor-alpha (TNF-alpha), although the possibility has been raised that the activity of LF in this regard was indirect and seconda ry to its ability to bind to and inactivate the bacterial lipopolysaccharid e (LPS) used to induce cytokine production. However, the identification of putative membrane receptors for LF raises the possibility that the interact ion of LF with its receptor may be one important route through which this p rotein exerts anti-inflammatory activity. In the present investigations the biological properties of LF have been examined in a model of cutaneous imm une function where the allergen-induced migration of epidermal Langerhans c ells (LC) from the skin and their subsequent accumulation as dendritic cell s (DC) in skin-draining lymph nodes are known to be dependent upon the de n ovo synthesis of TNF-alpha, but independent of exogenous LPS. Consistent wi th the protein having direct anti-inflammatory properties, it was found tha t the intradermal injection of recombinant murine LF (either iron-saturated or iron-depleted LF) inhibited significantly allergen (oxazolone) -induced LC migration and DC accumulation. That these inhibitory effects were secon dary to the inhibition of local TNF-alpha synthesis was suggested by the fi ndings that first, LF was unable to inhibit LC migration induced by intrade rmal injection of TNF-alpha itself, and second, that migration stimulated b y local administration of another epidermal cytokine, interleukin 1 beta, w hich is also dependent upon TNF-alpha production, was impaired significantl y by prior treatment with LF. Finally, immunohistochemical analyses demonst rated the presence of LF in skin, associated primarily with keratinocytes. Collectively these data support the possession by LF of direct immunomodula tory and/or anti-inflammatory activity, probably associated in this case wi th inhibition of cytokine production. Furthermore, the results suggest that as a constituent of normal skin, LF may play a role in homeostatic regulat ion of cutaneous immune function.