IκBζ is a key transcriptional regulator of IL-36-driven psoriasis-related gene expression in keratinocytes
Open Access
- 2 October 2018
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 115 (40), 10088-10093
- https://doi.org/10.1073/pnas.1801377115
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 TNF alpha 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 I kappa B zeta an atypical I kappa B member and a specific transcriptional regulator of selective NF-kappa B target genes. Induction of I kappa B zeta by IL-36 was mediated by NF-kappa B and STAT3. In agreement, IL-36-mediated induction of I kappa B zeta was found to be required for the expression of various psoriasis-related genes involved in inflammatory signaling, neutrophil chemotaxis, and leukocyte activation. Importantly, I kappa B zeta-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 I kappa B zeta mRNA was highly up-regulated in biopsies of psoriasis patients where it coincided with IL-36G levels. Thus our results uncover an important role for I kappa B zeta in IL-36 signaling and validate I kappa B zeta as an attractive target for psoriasis therapy.Keywords
Funding Information
- Bundesministerium für Bildung und Forschung (01FP09104B)
- Deutsche Forschungsgemeinschaft (SFB/TR 156)
- Deutsche Forschungsgemeinschaft (SFB/TR 209)
- Deutsche Forschungsgemeinschaft (Emmy-Noether)
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