Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Oct 27;112(43):E5825-33. doi: 10.1073/pnas.1509971112. Epub 2015 Oct 12.

IκBζ is a key driver in the development of psoriasis.

Author information

1
Department of Dermatology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark; claus.johansen@clin.au.dk.
2
Department of Dermatology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark;
3
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, D-72076 Tübingen, Germany;
4
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, D-72076 Tübingen, Germany; German Cancer Consortium and German Cancer Research Center, 69120 Heidelberg, Germany.

Abstract

Psoriasis is a common immune-mediated, chronic, inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although TNFα- and IL-17A-targeting drugs have recently proven to be highly effective, the molecular mechanism underlying the pathogenesis of psoriasis remains poorly understood. We found that expression of the atypical IκB member IκB (inhibitor of NF-κB) ζ, a selective coactivator of particular NF-κB target genes, was strongly increased in skin of patients with psoriasis. Moreover, in human keratinocytes IκBζ was identified as a direct transcriptional activator of TNFα/IL-17A-inducible psoriasis-associated proteins. Using genetically modified mice, we found that imiquimod-induced psoriasis-like skin inflammation was completely absent in IκBζ-deficient mice, whereas skin inflammation was still inducible in IL-17A- and TNFα-deficient mice. IκBζ deficiency also conferred resistance against IL-23-induced psoriasis. In addition, local abrogation of IκBζ function by intradermal injection of IκBζ siRNA abolished psoriasis-like skin inflammation. Taken together, we identify IκBζ as a hitherto unknown key regulator of IL-17A-driven effects in psoriasis. Thus, targeting IκBζ could be a future strategy for treatment of psoriasis, and other inflammatory diseases for which IL-17 antagonists are currently tested in clinical trials.

KEYWORDS:

IκBζ; cytokines; inflammation; psoriasis

PMID:
26460049
PMCID:
PMC4629387
DOI:
10.1073/pnas.1509971112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center