Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 40, Pages 10088-10093Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1801377115
Keywords
NFKBIZ; keratinocytes; psoriasis; I kappa B zeta
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Funding
- Emmy-Noether program of the Deutsche Forschungsgemeinschaft
- German Ministry for Education and Research Grant of the Network for Autoinflammatory Disorders in Children and Adolescents [01FP09104B]
- [Sonderforschungsbereich/Transregio SFB/TR 156]
- [SFB/TR 209]
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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.
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