IκBζ is a key player in the anti-psoriatic effects of secukinumab

Abstract Background IκBζ plays a key role in psoriasis by mediating IL-17A-driven effects, but the molecular mechanism by which IL-17A regulates IκBζ expression is not clarified. Objective To explore the molecular transformation in psoriatic patients during anti-IL-17A (secukinumab) treatment with focus on IκBζ. Methods The study was an open-label, one arm, single center secukinumab treatment study that included 14 patients with plaque psoriasis. Skin biopsies and blood samples were collected on day 0, 4, 14, 42 and 84; and processed for microarray gene expression analysis. Furthermore, in vitro experiments with human keratinocytes and synovial fibroblasts were conducted. Results Secukinumab improved clinical scores and histological psoriasis features. Moreover, secukinumab altered the skin transcriptome. The major transcriptional shift appeared between day 14 and day 42 after treatment initiation, though already at day four, 80 genes were differentially expressed. NFKBIZ (the gene encoding IκBζ) was reduced already after four days of treatment in the skin. NFKBIZ expression correlated to PASI, and NFKBIZ mRNA levels in the skin decreased during anti-IL-17A treatment. Moreover, specific NFKBIZ signature genes were significantly altered during anti-IL-17A treatment. Finally, we identified Act1, p38 MAPK, JNK, and NF-κB as key signaling pathways in NFKBIZ/IκBζ regulation. Conclusion Our results define a crucial role for IκBζ in the anti-psoriatic effect of secukinumab. Because IκBζ signature genes were regulated already after four days of treatment, this strongly indicates that IκBζ plays a crucial role for the anti-psoriatic effects mediated by anti-IL-17A treatment.