Epidermal Structure & Barrier Function

Abstract

The disturbed skin barrier plays an important role in the pathogenesis of atopic dermatitis. The development of the skin barrier malfunction in atopic dermatitis is not fully understood. Besides loss of function mutations in the filaggrin gene in about 30% of the patients there are data suggesting a secondary impairment of the skin barrier by mediators of inflammation. This includes reduction of the expression of filaggrin and filaggrin processing enzymes as shown for bleomycin hydrolase. In line with this we found decreased filaggrin expression in skin from patients with or without filaggrin mutations. Calpain I is another enzyme thought to be involved in late processing steps of filaggrin responsible for degrading deiminated filaggrin. In previous experiments with different proinflammatory cytokines we identified interferone (IFN) γ down regulating filaggrin expression in human keratinocyte cultures in a concentration dependent manner. Now we analyzed its time dependency and the influence of IFN γ and proinflammatory cytokines (such as interleukin 1β, 4, 5, 6, 13, 15, 17, 18, 20, 31, tumor necrosis factor α and tissue derived growth factor α) on calpain I expression. Analysis was semiquantitatively performed by real-time PCR. Filaggrin expression was reduced the most after 24 h. In contrast to its influence on filaggrin expression IFN γ it did not cause a significant decrease of calpain I expression. However a slight reduction of calpain I expression was detected after stimulation with interleukin 1β and 18, although not reaching statistical significance. Downregulation of filaggrin in inflammation by IFN γ might aggravate barrier disruption in psoriasis and atopic dermatitis.