Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: In order to better understand the IL-17A signaling pathway we have analyzed the effects of IL-17A in human primary synovial fibroblasts (SF), a major source of inflammatory mediators in rheumatoid arthritis (RA), as an example of stromal cells. We could show that IL-17A alone and in combination with TNF induces NFKBIZ encoding the NFκB pathway modulator IκBζ. In this study we assessed the role of NFKBIZ/IκBζ as a signaling node downstream of IL-17A by NFKBIZ siRNA knockdown. Since NFKBIZ has recently been identified as a psoriasis susceptibility locus, and shown to drive inflammation in psoriasis-like mouse models and in human keratinocytes, we analyzed the mRNA levels of NFKBIZ and of selected target genes in skin biopsies from psoriasis patients that have been treated with the anti-IL-17A antibody secukinumab (approved for the treatment of psoriasis and psoriatic arthritis).
Methods: Human primary RA-SF (Cell Application Inc.) were transfected with control or NFKBIZ siRNA (24h) before stimulation with IL-17A alone or in combination with TNF (18h). mRNA levels of inflammatory mediators (e.g. IL-6, CSF3/G-CSF, CXCL-1) were determined by qPCR, and released protein levels by AlphaLISA or homogeneous time resolved fluorescence. Secukinumab was added prior to TNF/IL-17A to determine its neutralizing activity. The mRNA levels of NFKBIZ and target genes in lesional and nonlesional skin biopsies from psoriasis patients at baseline and after 12 week treatment with secukinumab (n=19) or placebo (n=9) were determined by Nanostring.
Conclusion: We show that NFKBIZ is induced in psoriatic lesional skin and by IL-17A alone and in combination with TNF in synovial fibroblasts. We demonstrate that NFKBIZ controls the expression of IL-17A-stimulated main inflammatory mediators. We also observe that mRNA levels of NFKBIZ, CXCL-1 and of the gene encoding β-defensin2 are reduced in lesional skin from psoriasis patients after secukinumab treatment. These data suggest that the therapeutic effect of secukinumab seen in psoriasis and potentially other indications may be mediated at least in part by the downregulation of the NFKBIZ signaling node.
To cite this abstract in AMA style:Hennze R, Schlitt T, Peters T, Koroleva I, Torene R, Jiang X, Curcic Djuric M, Mir A, Kolbinger F, Huppertz C. The Anti-IL-17A Antibody Secukinumab (Cosentyx®, AIN457) Diminishes the Expression of the NFκB Pathway Modulator Iκbζ [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/the-anti-il-17a-antibody-secukinumab-cosentyx-ain457-diminishes-the-expression-of-the-nf%ce%bab-pathway-modulator-i%ce%bab%ce%b6/. Accessed March 22, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-anti-il-17a-antibody-secukinumab-cosentyx-ain457-diminishes-the-expression-of-the-nf%ce%bab-pathway-modulator-i%ce%bab%ce%b6/