| First Author | Müller A | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 40 | Pages | 10088-10093 |
| PubMed ID | 30224457 | Mgi Jnum | J:266673 |
| Mgi Id | MGI:6201661 | Doi | 10.1073/pnas.1801377115 |
| Citation | Muller A, et al. (2018) IkappaBzeta is a key transcriptional regulator of IL-36-driven psoriasis-related gene expression in keratinocytes. Proc Natl Acad Sci U S A 115(40):10088-10093 |
| abstractText | 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 TNFalpha 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 IkappaBzeta, an atypical IkappaB member and a specific transcriptional regulator of selective NF-kappaB target genes. Induction of IkappaBzeta by IL-36 was mediated by NF-kappaB and STAT3. In agreement, IL-36-mediated induction of IkappaBzeta was found to be required for the expression of various psoriasis-related genes involved in inflammatory signaling, neutrophil chemotaxis, and leukocyte activation. Importantly, IkappaBzeta-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 IkappaBzeta mRNA was highly up-regulated in biopsies of psoriasis patients where it coincided with IL36G levels. Thus our results uncover an important role for IkappaBzeta in IL-36 signaling and validate IkappaBzeta as an attractive target for psoriasis therapy. |
