2. Academic Validation
  3. Immunoproteasome inhibitor DPLG3 attenuates experimental colitis by restraining NF-κB activation

Immunoproteasome inhibitor DPLG3 attenuates experimental colitis by restraining NF-κB activation

  • Biochem Pharmacol. 2020 Jul;177:113964. doi: 10.1016/j.bcp.2020.113964.
Rezvan Moallemian 1,  Ashfaq Ur Rehman 2,  Na Zhao 1,  Huan Wang 1,  Haifeng Chen 2,  Gang Lin 3,  Xiaojing Ma 4,  Jing Yu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2 State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 3 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, United States.
  • 4 State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, United States. Electronic address: xim2002@sjtu.edu.cn.
  • 5 State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: jingyu@sjtu.edu.cn.
PMID: 32278007 DOI: 10.1016/j.bcp.2020.113964
Abstract

Inflammatory bowel disease is a chronic and pathologic autoimmune condition. And immunoproteasome is becoming an attractive therapeutic target for autoimmune inflammatory diseases. In this study, we evaluated the therapeutic effects of a specific small molecule inhibitor of the chymotryptic-like β5i subunits of the immunoproteasome, DPLG3, in a preclinical murine colitis model and explored the underlying molecular mechanism for the immune suppression. DPLG3 showed significant effects in attenuating the disease progression in experimental colitis, reducing the body and spleen weight losses, and colon length shortening compared to vehicle-treated controls and to the well studied immunoproteasome inhibitor ONX-0914. Mechanistically, DPLG3 decreased inflammatory cytokines and the influx of effector T cells and macrophages in colon tissues while increasing the number of regulatory T cells. Molecular docking analysis of the protein-ligand interaction profile revealed that the β5i-DPLG3 complex was more stable and efficient in the binding sites compared to those formed with ONX-0914 and LU-005i. Furthermore, DPLG3 reduced the protein levels of the canonical NF-κB p50 and p65, as well as the nuclear p65. Thus, DPLG3 constitutes a potentially efficacious clinical agent for autoimmune inflammatory diseases.

Keywords

Colitis; DPLG3; Immunoproteasome; Inflammatory bowel disease; NF-κB.

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