423 STAT 3 and its role in the cutaneous defense

Our study is based on the Hyper-IgE syndrome (HIES) which is a primary immunodeficiency due to a mutation in the STAT3-gene (“signal transducer and activator of transcription 3”). Patients suffer from severe skin infections mainly caused by Staphylococcus aureus (SA). It has been shown that the STAT3-mutation decreases the differentiation of T-cells into TH17-cells which are especially important for the activation of the skin’s defense system. This provides an explanation why HIES-patients are highly susceptible to skin infections. Beyond that we questioned if the STAT3-mutation also affects keratinocytes themselves in their innate defense system. Therefore we examined keratinocytes regarding both the gene expression of antimicrobial peptides (AMPs) which are physiologically involved in the killing of SA (hBD-3 and RNase 7) and the gene expression of IL-17C, an important cytokine produced by keratinocytes. Primary keratinocytes were cultured with a STAT3 Inhibitor or with a STAT3 siRNA to mimic the STAT3-dysregulation of HIES-patients in vitro. Subsequently the keratinocytes were stimulated with living SA overnight. Afterwards the RNA was isolated and reverse transcribed into cDNA which served as a target for the “real-time” PCR to quantify the gene expression of AMPs and IL-17C. Our results show a SA-mediated gene induction of hBD-3, RNase 7 and IL-17C. This induction was decreased by blocking STAT3 with a STAT3 inhibitor or a STAT3 siRNA which indicates that the SA-induced expression of those genes is mediated by STAT3. Based on our data we assume that IL-17C, hBD-3 and RNase 7 are less induced during the infection with SA in keratinocytes of HIES-patients. A decreased induction of IL-17C may lead to a reduced activation of the skin's defense system. Since hBD-3 and RNase 7 have the capacity to kill SA, one may hypothesize that the failure to adequately induce these genes leads to increased infections with this pathogen. Our findings could initiate further research in this field and may lead to novel treatment options for HIES-patients by the application of AMPs.