IκBζ is a key player in the antipsoriatic effects of secukinumab

TY - JOUR

T1 - IκBζ is a key player in the antipsoriatic effects of secukinumab

AU - Bertelsen, Trine

AU - Ljungberg, Christine

AU - Litman, Thomas

AU - Huppertz, Christine

AU - Hennze, Robert

AU - Rønholt, Kirsten

AU - Iversen, Lars

AU - Johansen, Claus

N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

KW - IL-17A

KW - IκBζ

KW - NF-κB activator 1

KW - NFKBIZ

KW - Secukinumab

KW - c-Jun

KW - keratinocytes

KW - nuclear factor κB

KW - p38 mitogen-activated protein kinase

KW - psoriasis

U2 - 10.1016/j.jaci.2019.09.029

DO - 10.1016/j.jaci.2019.09.029

M3 - Journal article

C2 - 31622687

SN - 0091-6749

VL - 145

SP - 379

EP - 390

JO - The Journal of allergy and clinical immunology

JF - The Journal of allergy and clinical immunology

IS - 1

ER -