دورية أكاديمية
ABD-Derived Protein Blockers of Human IL-17 Receptor A as Non-IgG Alternatives for Modulation of IL-17-Dependent Pro-Inflammatory Axis
| العنوان: | ABD-Derived Protein Blockers of Human IL-17 Receptor A as Non-IgG Alternatives for Modulation of IL-17-Dependent Pro-Inflammatory Axis |
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| المؤلفون: | Marie Hlavničková, Milan Kuchař, Radim Osička, Lucie Vaňková, Hana Petroková, Michal Malý, Jiří Černý, Petr Arenberger, Petr Malý |
| المصدر: | International Journal of Molecular Sciences, Vol 19, Iss 10, p 3089 (2018) |
| بيانات النشر: | MDPI AG, 2018. |
| سنة النشر: | 2018 |
| المجموعة: | LCC:Biology (General) LCC:Chemistry |
| مصطلحات موضوعية: | binding protein, albumin-binding domain, cytokine, IL-17 receptor, combinatorial library, Biology (General), QH301-705.5, Chemistry, QD1-999 |
| الوصف: | Interleukin 17 (IL-17) and its cognate receptor A (IL-17RA) play a crucial role in Th17 cells-mediated pro-inflammatory pathway and pathogenesis of several autoimmune disorders including psoriasis. IL-17 is mainly produced by activated Th-17 helper cells upon stimulation by IL-23 and, via binding to its receptors, mediates IL-17-driven cell signaling in keratinocytes. Hyper-proliferation of keratinocytes belongs to major clinical manifestations in psoriasis. To modulate IL-17-mediated inflammatory cascade, we generated a unique collection of IL-17RA-targeting protein binders that prevent from binding of human IL-17A cytokine to its cell-surface receptor. To this goal, we used a highly complex combinatorial library derived from scaffold of albumin-binding domain (ABD) of streptococcal protein G, and ribosome display selection, to yield a collection of ABD-derived high-affinity ligands of human IL-17RA, called ARS binders. From 67 analyzed ABD variants, 7 different sequence families were identified. Representatives of these groups competed with human IL-17A for binding to recombinant IL-17RA receptor as well as to IL-17RA-Immunoglobulin G chimera, as tested in enzyme-linked immunosorbent assay (ELISA). Five ARS variants bound to IL-17RA-expressing THP-1 cells and blocked binding of human IL-17 cytokine to the cell surface, as tested by flow cytometry. Three variants exhibited high-affinity binding with a nanomolar Kd value to human keratinocyte HaCaT cells, as measured using Ligand Tracer Green Line. Upon IL-17-stimulated activation, ARS variants inhibited secretion of Gro-α (CXCL1) by normal human skin fibroblasts in vitro. Thus, we identified a novel class of inhibitory ligands that might serve as immunosuppressive IL-17RA-targeted non-IgG protein antagonists. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1422-0067 |
| العلاقة: | http://www.mdpi.com/1422-0067/19/10/3089Test; https://doaj.org/toc/1422-0067Test |
| DOI: | 10.3390/ijms19103089 |
| الوصول الحر: | https://doaj.org/article/ed479f3c9429488a9dddbbfef8b0e86eTest |
| رقم الانضمام: | edsdoj.479f3c9429488a9dddbbfef8b0e86e |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14220067 |
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| DOI: | 10.3390/ijms19103089 |