I?B? is a key player in the antipsoriatic effects of secukinumab - 05/01/20
, Christine Ljungberg, MD a, Thomas Litman, PhD b, Christine Huppertz, PhD c, Robert Hennze, DMSc c, Kirsten Rønholt, MD, PhD a, Lars Iversen, MD, DMSc a, Claus Johansen, PhD, DMSc aAbstract |
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 |
We sought to explore the molecular transformation in patients with psoriasis during anti-IL-17A (secukinumab) treatment with a focus on IκBζ.
Methods |
The study was an open-label, single-arm, single-center secukinumab treatment study that included 14 patients with plaque psoriasis. Skin biopsy specimens and blood samples were collected on days 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 histologic psoriasis features. Moreover, secukinumab altered the skin transcriptome. The major transcriptional shift appeared between day 14 and day 42 after treatment initiation, although 80 genes were differentially expressed already at day 4. Expression of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor (IκB) ζ (NFKBIZ, the gene encoding IκBζ) was reduced already after 4 days of treatment in the skin. NFKBIZ expression correlated to Psoriasis Area and Severity Index score, 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 NF-κB activator 1 (Act1), p38 mitogen-activated protein kinase (MAPK), Jun NH2-terminal kinase (JNK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) as key signaling pathways in NFKBIZ/IκBζ regulation.
Conclusion |
Our results define a crucial role for IκBζ in the antipsoriatic effect of secukinumab. Because IκBζ signature genes were regulated already after 4 days of treatment, this strongly indicates that IκBζ plays a crucial role in the antipsoriatic effects mediated by anti–IL-17A treatment.
Le texte complet de cet article est disponible en PDF.Key words : Secukinumab, psoriasis, IL-17A, NFKBIZ, IκBζ, keratinocytes, c-Jun, NF-κB activator 1, p38 mitogen-activated protein kinase, nuclear factor κB
Abbreviations used : Act1, DEG, DMSO, ERK, IL-17RA, JNK, MAPK, NF-κB, NFKBIZ, PASI, SF, siRNA
Plan
| Supported by Novartis, the Danish Psoriasis Research Society, the A.P. Moeller Foundation, the Aage Bang foundation, and the Wehnerts Foundation. |
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| Disclosure of potential conflict of interest: T. Litman is partly funded by Leo Pharma. C. Huppertz and R. Hennze are employees of Novartis Pharma AG. L. Iversen served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Almirall, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, Janssen Cilag, Kyowa, Leo Pharma, MSD, Novartis, Pfizer, Samsung, and UCB. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 145 - N° 1
P. 379-390 - janvier 2020 Retour au numéro
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