Cytokine-induced expression of transforming growth factor-alpha and the epidermal growth factor receptor in neonatal skin explants

Abstract

Hyperproliferative diseases of the epidermal keratinocytes, such as psoriasis vulgaris, are characterized by overexpression and altered distribution of the epidermal growth factor/transforming growth factor (EGF/TGF)-alpha receptor, and of TGF-alpha itself. It is believed that overexpression of this lignad/receptor system contributes to the hyperproliferative state of keratinocytes in an autocrine fashion. However, little is known about the factors that regulate expression of the EGF/TGF-alpha receptor, as well as expression of TGF-alpha in stratified epithelium. We examined modulation of the immunoreactive EGF/TGF-alpha receptor and TGF-alpha expression in normal neonatal foreskin explants by a variety of cytokines present in psoriatic lesions. Human (hu) recombinant (r) tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma induced EGF/TGF-alpha receptor and TGF-alpha expression by keratinocytes as determined by immunohistochemistry. Neutralizing antibodies to TNF-alpha and IFN-gamma inhibited upregulation of EGF/TGF-alpha receptors and TGF-alpha by the respective cytokines. Interleukin (IL)-8 induced expression of TGF-alpha, but not of its receptor. Other cytokines (TNF-beta, IFN-beta, IL-1 alpha, IL-2, IL-3, IL-5, IL-6, granulocyte/macrophage colony-stimulating factor, and macrophage colony-stimulating factor) did not alter the expression patterns of EGF/TGF-alpha receptors or TGF-alpha in normal neonatal skin explants. These experiments demonstrate that specific cytokines known to be present in psoriatic lesions can induce normal epidermis to express TGF-alpha and its receptor in a pattern similar to that observed in psoriatic skin.