Development of an inflammatory tissue-selective chimeric TNF receptor

Chia Jung Lee, Chao Ching Wang, Michael Chen, Kuo Hsiang Chuang, Tian Lu Cheng, Ting Yan Jian, Yun Ming Wang, Tse Hung Huang, Kuang Wen Liao, Shey Cherng Tzou

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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.

Original languageEnglish
Pages (from-to)340-346
Number of pages7
JournalCytokine
Volume113
DOIs
Publication statusPublished - Jan 1 2019

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Keywords

  • Chimeric TNF receptor
  • Inflammation
  • Matrix metalloproteinase (MMP)
  • Tumor necrosis factor-α/receptor (TNF-α/TNFR)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Biochemistry
  • Hematology
  • Molecular Biology

Cite this

Lee, C. J., Wang, C. C., Chen, M., Chuang, K. H., Cheng, T. L., Jian, T. Y., Wang, Y. M., Huang, T. H., Liao, K. W., & Tzou, S. C. (2019). Development of an inflammatory tissue-selective chimeric TNF receptor. Cytokine, 113, 340-346. https://doi.org/10.1016/j.cyto.2018.10.003