Development of an inflammatory tissue-selective chimeric TNF receptor. (January 2019)

• Record Type: Journal Article
• Authors: Lee, Chia-Jung; Wang, Chao-Ching; Chen, Michael; Chuang, Kuo-Hsiang; Cheng, Tian-Lu; Jian, Ting-Yan; Wang, Yun-Ming; Huang, Tse-Hung; Liao, Kuang-Wen; Tzou, Shey-Cherng
• Is Part Of: Cytokine. Volume 113(2019)
• Page Start: 340
• Page End: 346
• Publication Date: 2019-01
• Subjects: Tumor necrosis factor-α/receptor (TNF-α/TNFR) -- Inflammation -- Matrix metalloproteinase (MMP) -- Chimeric TNF receptor; TNF Tumor Necrosis Factor -- TNFR Tumor Necrosis Factor Receptor -- MMP Matrix Metalloproteinase -- FDA Food and Drug Administration -- RANKL Receptor Activator of Nuclear Factor Kappa-B Ligand -- BAFF B-cell Activating Factor; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2018.10.003
• Languages: English
• ISSNs: 1043-4666

Abstract

Abstract: Background: Inhibiting TNF-α is an effective therapy for inflammatory diseases such as rheumatoid arthritis. However, systemic, nondiscriminatory neutralization of TNF-α is associated with considerable adverse effects. Methods: Here, we developed a trimeric chimeric TNF receptor by linking an N-terminal mouse Acrp30 trimerization domain and an MMP-2/9 substrate sequence to the mouse extracellular domain of TNF receptor 2 followed by a C-terminal mouse tetranectin coiled-coil domain (mouse Acrp-MMP-TNFR-Tn). Results: Here, we show that the Acrp30 trimerization domain inhibited the binding activity of TNFR, possibly by closing the binding site of the trimeric receptor. Cleavage of the substrate sequence by MMP-9, an enzyme highly expressed in inflammatory sites, restored the binding activity of the mouse TNF receptor. We also constructed a recombinant human chimeric TNF receptor (human Acrp-MMP-TNFR-Tn) in which an MMP-13 substrate sequence was used to link the human Acrp and the human TNF receptor 2. Human Acrp-MMP-TNFR-Tn showed reduced binding activity, and MMP-13 digestion recovered its binding activity with TNF-α. Conclusion: Acrp-masked chimeric TNF receptors may be able to be used for inflammatory tissue-selective neutralization of TNF-α to reduce the adverse effects associated with systemic neutralization of TNF-α.