(from the application): Interleukin 5 (IL-5) has been shown to be an important component of the cytokine regulatory network that controls peripheral eosinophil numbers and their recruitment/survivability at sites of inflammation. To understand better the role of IL-5 in cutaneous disease we have generated several transgenic lines of mice constitutively expressing a murine IL-5 gene in basal keratinocytes. Expression of IL-5 was restricted to this cell type using the regulatory elements of the human keratin-14 gene. The resulting mice appear to have a characteristic phenotype which includes a mild peripheral blood eosinophilia and a significant increase in resident cutaneous eosinophil infiltrates. Transgenic animals also show evidence of an increased frequency of hair-loss (alopecia). In addition, a subset of these animals spontaneously develop necrosing ulcerations of the skin. An important objective of this proposal is to augment ongoing studies of murine eosinophils by developing/characterizing a mouse model of eosinophil-mediated skin pathology to assess physiologically relevant effector functions in vivo. These effector functions will be tested in part through an evaluation of the transgenic mice as well as the response of these animals in established models of chemically-or allergen-induced inflammation. A long-term objective of this proposal is to integrate our molecular and mouse model approaches to understand eosinophil effector function with the downstream pathophysiological consequences of the recruitment and activation of this cell type in the skin.
The specific aims of this proposal are: (1) The characterization of the molecular, cellular, and histopathological changes in a transgenic mouse line (NJ.692) expressing IL-5 in the skin using a human keratin-14 (K14) promoter (i.e., basal keratinocytes); (2) Evaluate and quantify the response of NJ.692 transgenic mice in experimental models of chemical- (Croton oil exposure) or allergen-(aerosolized ragweed pollen induced cutaneous type I hypersensitivity) induced inflammation as well as contact hypersensitivity reactions (Oxazolone exposure); (3) Characterization of the cell adhesion molecule (L-selectin, P-selectin, E-selectin, ICAM or VLA-4) dependence of eosinophil recruitment to the skin.
