The relevance of TNFAIP3 in cutanous defense

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Antimicrobial peptides (AMP) are important effector molecules in epithelial defense. They are promptly induced by contact with microorganisms and antimicrobial effective in low concentrations. In our research on signal transduction of AMP we got hints that the human regulator protein TNFAIP3, which was originally found due to its protecting properties in TNF-alpha induced apoptosis, inhibits the bacteria-induced expression of AMP in keratinocytes. TNFAIP3 also seems to negatively regulate the bacterial induction of proinflammatory cytokines like IL-17C. Furthermore we have preliminary results that the expression of TNFAIP3 in keratinocytes is up regulated after infection with Staphylococcus aureus and Pseudomonas aeruginosa. Taken together these results lead to our hypothesis that bacteria are able to upregulate the human regulatory protein TNFAIP3, leading to decreased expression of defense molecules like AMP and cytokines, which implies advantages for the bacterias survival. In the requested project we want to prove this hypothesis. Antimicrobial peptides and cytokines are moreover strongly up regulated in the common inflammatory skin disease psoriasis. Furthermore psoriasis-associated TNFAIP3-gene polymorphisms exist. We want to investigate a potential relation between expression level of TNFAIP3 and concentrations of AMP and psoriasis-associated cytokines in the requested project. However in atopic dermatitis (AD) the expression of AMP is lower and AD-patients are - in contrast to psoriasis patients - prevalently affected with S. aureus infections. To date there are no studies about a correlation between TNFAIP3 and atopic dermatitis. Based on our preliminary results we hypothesize an increased TNFAIP3-expression in skin of atopic dermatitis patients, which would accompany with lower AMP-expression levels. We also want to investigate this point in the requested project to support new information for potential new therapeutic approaches.