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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.

Author information

1
Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
2
Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany.
3
German Cancer Consortium, German Cancer Research Center, 69120 Heidelberg, Germany.
4
Interfaculty Institute for Biochemistry, University of Tübingen, 72076 Tübingen, Germany; daniela.kramer@uni-tuebingen.de.

Abstract

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.

KEYWORDS:

IL-36; IκBζ; NFKBIZ; keratinocytes; psoriasis

PMID:
30224457
PMCID:
PMC6176600
DOI:
10.1073/pnas.1801377115
[Indexed for MEDLINE]
Free PMC Article

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