The central role of the transcriptional regulator IκBζ in psoriasis

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Dokumentart: Dissertation
Date: 2020-11-17
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biochemie
Advisor: Schulze-Osthoff, Klaus (Prof. Dr.)
Day of Oral Examination: 2020-11-10
DDC Classifikation: 000 - Computer science, information and general works
500 - Natural sciences and mathematics
570 - Life sciences; biology
Keywords: Schuppenflechte
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IκBζ belongs to the group of atypical NF-κB inhibitors (IκBs). In contrast to classical IκBs, IκBζ is only inducibly expressed in the cell nucleus, where it can inhibit, but more importantly, also activate the expression of a particular subset of target genes. NFKBIZ, the gene encoding IκBζ, has been identified as new risk gene in psoriasis. Moreover, IκBζ knockout mice are protected in certain models of experimental psoriasis. The aim of this thesis was to examine the global role of IκBζ in psoriasis in order to find a new therapy approach. It could be shown that IκBζ is a regulator not only of IL-17 but also of IL-36 signaling, which plays a major role in certain forms of psoriasis. The IL-36-mediated induction of IκBζ was driven by NF-κB and STAT3, and led to the expression of pro-inflammatory genes that initiate the development of psoriasis. Accordingly, IκBζ knockout mice were completely protected from IL-36- mediated experimental psoriasis. Thus, IκBζ represents a central regulator in psoriasis, which promotes inflammation regardless of the type of stimulus. Based on this finding, screenings for small-molecule inhibitors were performed that are able to repress the induction of IκBζ. Thereby, I could identify a new pro-inflammatory signal pathway in keratinocytes. In this pathway, CDK4/6 phosphorylated the methyltransferase EZH2, which in turn methylated and activated STAT3, which transcriptionally induced IκBζ. The pharmacological inhibition of CDK4/6 or EZH2 inhibited the pathogenesis of psoriasis in vitro and in vivo. In conclusion, this thesis not only validates IκBζ as an essential mediator of psoriasis, but also identifies the CDK4/6-EZH2 axis as a novel mechanism whose inhibition could provide a potential therapeutic option for the treatment of psoriasis.

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