I?B? is a key transcriptional regulator of IL-36-driven psoriasis-related gene expression in keratinocytes.

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? 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?B?, an atypical I?B member and a specific transcriptional regulator of selective NF-?B target genes. Induction of I?B? by IL-36 was mediated by NF-?B and STAT3. In agreement, IL-36-mediated induction of I?B? was found to be required for the expression of various psoriasis-related genes involved in inflammatory signaling, neutrophil chemotaxis, and leukocyte activation. Importantly, I?B?-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?B? mRNA was highly up-regulated in biopsies of psoriasis patients where it coincided with IL36G levels. Thus our results uncover an important role for I?B? in IL-36 signaling and validate I?B? as an attractive target for psoriasis therapy.

SUBMITTER: Muller A 

PROVIDER: S-EPMC6176600 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature