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IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes
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 targe...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176600/ https://www.ncbi.nlm.nih.gov/pubmed/30224457 http://dx.doi.org/10.1073/pnas.1801377115 |
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author | Müller, Anne Hennig, André Lorscheid, Sebastian Grondona, Paula Schulze-Osthoff, Klaus Hailfinger, Stephan Kramer, Daniela |
author_facet | Müller, Anne Hennig, André Lorscheid, Sebastian Grondona, Paula Schulze-Osthoff, Klaus Hailfinger, Stephan Kramer, Daniela |
author_sort | Müller, Anne |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6176600 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-61766002018-10-11 IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes Müller, Anne Hennig, André Lorscheid, Sebastian Grondona, Paula Schulze-Osthoff, Klaus Hailfinger, Stephan Kramer, Daniela Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2018-10-02 2018-09-17 /pmc/articles/PMC6176600/ /pubmed/30224457 http://dx.doi.org/10.1073/pnas.1801377115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Müller, Anne Hennig, André Lorscheid, Sebastian Grondona, Paula Schulze-Osthoff, Klaus Hailfinger, Stephan Kramer, Daniela IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes |
title | IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes |
title_full | IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes |
title_fullStr | IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes |
title_full_unstemmed | IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes |
title_short | IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes |
title_sort | iκbζ is a key transcriptional regulator of il-36–driven psoriasis-related gene expression in keratinocytes |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176600/ https://www.ncbi.nlm.nih.gov/pubmed/30224457 http://dx.doi.org/10.1073/pnas.1801377115 |
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