INTRADERMAL TRANSGENIC EXPRESSION OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR INDUCES NEUTROPHILIA, EPIDERMAL HYPERPLASIA, LANGERHANS CELL MACROPHAGE ACCUMULATION, AND DERMAL FIBROSIS

Granulocyte-macrophage colony-stimulating factor (GM-CSF), a !pleiotro pic cytokine, is up-regulated in a number of chronic skin inflammatory diseases, particularly atopic dermatitis. However, its role in these conditions remains largely unclear. To explore its function, we have e stablished a rat intradermal transgene model by using a replication-de ficient adenoviral vector expressing GM-CSF. Intradermal GM-CSF gene t ransfer led to a prolonged compartmentalized expression of transgene p rotein in the dermis. This expression induced an unexpectedly wide spe ctrum of pathologies in both epidermis and dermis, including neutrophi lia, epidermal hyperplasia (acanthosis), an increased number of epider mal Langerhans' cells, accumulation of MHC Ii-positive macrophages, as well as mild eosinophilia in the dermis at earlier stages and upper d ermal fibrosis at later stages. These findings thus identify GM-CSF as a potent multifunctional cytokine at skin site that is capable of evo lving numerous inflammatory processes ranging from the early acute neu trophilia to later chronic fibrotic responses, and also suggest the im portant role of this cytokine in the development and perpetuation of p athologic changes in chronic skin inflammatory conditions including ch ronic atopic dermatitis. In addition, our study presents a novel model of adult normal animals that is useful for identifying and studying k ey cytokines involved in inflammatory skin diseases.