Journal
CYTOKINE
Volume 113, Issue -, Pages 340-346Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.cyto.2018.10.003
Keywords
Tumor necrosis factor-alpha/receptor (TNF-alpha/TNFR); Inflammation; Matrix metalloproteinase (MMP); Chimeric TNF receptor
Funding
- Ministry of Science and Technology, Taiwan [MOST-105-2320-B-009-002]
- Aim for the Top University Plan from the Ministry of Education, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) from the Featured Areas Research Center Program by the Ministry of Education, Taiwan
- Ministry of Science and Technology [MOST105-2314-B-182A-133]
- Chang-Gung Memorial Hospital Research Foundation [CMRPG2F0141 -2, CMRPG2H0121]
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Background: Inhibiting TNF-alpha is an effective therapy for inflammatory diseases such as rheumatoid arthritis. However, systemic, nondiscriminatory neutralization of TNF-alpha 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-alpha. Conclusion: Acrp-masked chimeric TNF receptors may be able to be used for inflammatory tissue-selective neutralization of TNF-alpha to reduce the adverse effects associated with systemic neutralization of TNF-alpha.
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