Neurotrophin-4 production by human epidermal keratinocytes: increased expression in atopic dermatitis

Chronic inflammatory conditions of human skin, such as prurigo lesions of atopic dermatitis, are characterized clinically by intense pruritus and histologically by increased innervation. Regulation of skin innervation is thought to depend on neurotrophic factors. In this study, human skin cells were identified as a source of neurotrophins. Cultured keratinocytes expressed neurotrophin-4, whereas dermal fibroblasts expressed neurotrophin-3. In vitro stimulation with interferon-gamma, a marker cytokine for atopic eczema, induced keratinocyte neurotrophin-4 production, which was able to support growth of a neuroglioblastoma-derived cell line. In vivo, immunohistochemistry of human skin for neurotrophins showed neurotrophin-4 staining in the epidermal layer and neurotrophin-3 staining in the dermal compartment. Neurotrophin-4 but not neurotrophin-3 expression was markedly increased in interferon-gamma-injected skin. Prurigo lesions of atopic dermatitis skin were characterized by intense epidermal staining for neurotrophin-4, suggesting a pathophysiologic role for this neurotrophin in the increased innervation characteristic for these skin lesions. This study demonstrates differential expression and regulation of neurotrophins in human skin. It also identifies keratinocyte-derived neurotrophin-4 as a possible link between the immune and the nerve system of human skin.