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Intradermal
Transgenic Expression of Granulocyte-Macrophage Colony-Stimulating Factor
Induces Neutrophilia, Epidermal Hyperplasia, Langerhans' Cell/Macrophage
Accumulation, and Dermal Fibrosis |
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Heidi M. Sowter,
Anthony N. Corps, Amanda L. Evans, Dawn E. Zhou Xing, Jack Gauldie, Guy
M. Tremblay, Bryan R. Hewlett, and Christina Addison |
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Immunology
and Infection Program (ZX, JG, BRH, CA), Department of Pathology, Health
Sciences Centre, McMaster University, Hamilton, Ontario; and Unite de recherche
(GMT), Centre de Pneumologie, Hopital Laval, Sainte-Foy, Quebec, Canada |
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Granulocyte-macrophage colony-stimulating
factor (GM-CSF), a pleiotropic 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 established a rat intradermal transgene model by using a replication-deficient
adenoviral vector expressing GM-CSF. Intradermal GM-CSF gene transfer led
to a prolonged compartmentalized expression of transgene protein in the
dermis. This expression induced an unexpectedly wide spectrum of pathologies
in both epidermis and dermis, including neutrophilia, epidermal hyperplasia
(acanthosis), an increased number of epidermal Langerhans' cells, accumulation
of MHC II-positive macrophages, as well as mild eosinophilia in the dermis
at earlier stages and upper dermal fibrosis at later stages. These findings
thus identify GM-CSF as a potent multifunctional cytokine at skin site that
is capable of evolving numerous inflammatory processes ranging from the
early acute neutrophilia to later chronic fibrotic responses, and also suggest
the important role of this cytokine in the development and perpetuation
of pathologic changes in chronic skin inflammatory conditions including
chronic atopic dermatitis. In addition, our study presents a novel model
of adult normal animals that is useful for identifying and studying key
cytokines involved in inflammatory skin diseases. |
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