Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis

Abstract

background: Activation and skin-selective homing of T cells and effector functions in the skin represent sequential events in the pathogenesis of atopic dermatitis and allergic contact dermatitis. Objective: T cell-mediated keratinocyte apoptosis plays a key pathogenetic role in the formation of eczematous dermatitis. Ifn-γ released from activated T cells upregulates Fas on keratinocytes, which renders them susceptible to apoptosis. The lethal hit is given to keratinocytes by means of Fas ligand expressed on the T-cell surface or released to the inflammatory microenvironment. We sought to investigate whether drugs used for the treatment of eczematous disorders interfere with this pathogenic pathway. Methods: T cell-mediated, Fas-induced keratinocyte apoptosis in a keratinocyte-t cell coculture system serves as an in vitro model of eczematous dermatitis. We tested, in this model, whether immunomodulatory agents (dexamethasone, cyclosporine A, rapamycine, tacrolimus/fk506, intravenous immunoglobulin [ivig], and theophylline) are able to inhibit apoptosis of keratinocytes. Additionally, skin biopsy specimens from patients with untreated and successfully treated eczematous dermatitis were evaluated for keratinocyte apoptosis. Results: Dexamethasone, cyclosporine A, Fk506, rapamycine, and Ivig are inhibitors of keratinocyte apoptosis induced by activated T cells. This effect is mediated by 2 major mechanisms directed on T cells or keratinocytes. T-cell activation was mainly inhibited by dexamethasone, Fk506, cyclosporine A, and rapamycine. Interestingly, high-dose dexamethasone and Ivig directly inhibited Fas-mediated keratinocyte apoptosis. In vivo keratinocyte apoptosis was significantly reduced after successful topical treatment of eczematous lesions. Conclusion: These results demonstrate mechanisms of action of current treatment approaches and provide a future for more focused therapeutic applications.