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

doi:10.1016/j.cyto.2018.10.003

Development of an inflammatory tissue-selective chimeric TNF receptor

Cytokine. 2019 Jan:113:340-346. doi: 10.1016/j.cyto.2018.10.003. Epub 2018 Oct 21.

Authors

Affiliations

¹ Department of Biological Science and Technology, National Chiao Tung University, Taiwan.
² Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
³ Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei, Taiwan.
⁴ Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Biotechnology Research and Development of Translational Medicine, Taipei Medical University, Taipei, Taiwan.
⁵ Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
⁶ Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan.
⁷ Department of Biological Science and Technology, National Chiao Tung University, Taiwan; Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan; School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan; Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
⁹ Department of Biological Science and Technology, National Chiao Tung University, Taiwan; Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan; Center for Intelligent Drug Systems and Smart Bio-devices (IDS(2)B), National Chiao-Tung University, Hsinchu, Taiwan. Electronic address: liaonms@mail.nctu.edu.tw.
¹⁰ Department of Biological Science and Technology, National Chiao Tung University, Taiwan; Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan; Center for Intelligent Drug Systems and Smart Bio-devices (IDS(2)B), National Chiao-Tung University, Hsinchu, Taiwan. Electronic address: sctzou@gmail.com.

PMID: 30352759
DOI: 10.1016/j.cyto.2018.10.003

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.

Keywords: Chimeric TNF receptor; Inflammation; Matrix metalloproteinase (MMP); Tumor necrosis factor-α/receptor (TNF-α/TNFR).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adiponectin* / chemistry
Adiponectin* / genetics
Adiponectin* / metabolism
Animals
Cell Line
Humans
Matrix Metalloproteinase 13* / chemistry
Matrix Metalloproteinase 13* / genetics
Matrix Metalloproteinase 13* / metabolism
Matrix Metalloproteinase 2* / chemistry
Matrix Metalloproteinase 2* / genetics
Matrix Metalloproteinase 2* / metabolism
Matrix Metalloproteinase 9* / chemistry
Matrix Metalloproteinase 9* / genetics
Matrix Metalloproteinase 9* / metabolism
Mice
Organ Specificity
Protein Binding
Protein Domains
Protein Multimerization*
Receptors, Tumor Necrosis Factor, Type II* / chemistry
Receptors, Tumor Necrosis Factor, Type II* / genetics
Receptors, Tumor Necrosis Factor, Type II* / metabolism
Recombinant Fusion Proteins*
Tumor Necrosis Factor-alpha* / chemistry
Tumor Necrosis Factor-alpha* / metabolism

Substances

ADIPOQ protein, human
Adiponectin
Adipoq protein, mouse
Receptors, Tumor Necrosis Factor, Type II
Recombinant Fusion Proteins
Tnfrsf1b protein, mouse
Tumor Necrosis Factor-alpha
MMP13 protein, human
Matrix Metalloproteinase 13
Matrix Metalloproteinase 2
Mmp2 protein, mouse
Matrix Metalloproteinase 9
Mmp9 protein, mouse