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Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):10088-10093. doi: 10.1073/pnas.1801377115. Epub 2018 Sep 17.

IκBζ is a key transcriptional regulator of IL-36-driven psoriasis-related gene expression in keratinocytes.

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Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany.
German Cancer Consortium, German Cancer Research Center, 69120 Heidelberg, Germany.
Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany;


Proinflammatory cytokine signaling in keratinocytes plays a crucial role in the pathogenesis of psoriasis, a skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although IL-17A and TNFα are effective therapeutic targets in psoriasis, IL-36 has recently emerged as a proinflammatory cytokine. However, little is known about IL-36 signaling and its downstream transcriptional responses. Here, we found that exposure of keratinocytes to IL-36 induced the expression of IκBζ, an atypical IκB member and a specific transcriptional regulator of selective NF-κB target genes. Induction of IκBζ by IL-36 was mediated by NF-κB and STAT3. In agreement, IL-36-mediated induction of IκBζ was found to be required for the expression of various psoriasis-related genes involved in inflammatory signaling, neutrophil chemotaxis, and leukocyte activation. Importantly, IκBζ-knockout mice were protected against IL-36-mediated dermatitis, accompanied by reduced proinflammatory gene expression, decreased immune cell infiltration, and a lack of keratinocyte hyperproliferation. Moreover, expression of IκBζ mRNA was highly up-regulated in biopsies of psoriasis patients where it coincided with IL36G levels. Thus our results uncover an important role for IκBζ in IL-36 signaling and validate IκBζ as an attractive target for psoriasis therapy.


IL-36; IκBζ; NFKBIZ; keratinocytes; psoriasis

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