PMID- 37716163
OWN - NLM
STAT- MEDLINE
DCOM- 20231107
LR  - 20231107
IS  - 1878-1705 (Electronic)
IS  - 1567-5769 (Linking)
VI  - 124
IP  - Pt A
DP  - 2023 Nov
TI  - PR-957 retards rheumatoid arthritis progression and inflammation by inhibiting 
      LMP7-mediated CD4(+) T cell imbalance.
PG  - 110860
LID - S1567-5769(23)01185-2 [pii]
LID - 10.1016/j.intimp.2023.110860 [doi]
AB  - OBJECTIVE: Low molecular mass polypeptide 7 (LMP7) is an immunoproteasome subunit 
      that regulates T cell amplification, differentiation, and inflammation and is 
      involved in rheumatoid arthritis (RA) progression. This study intended to apply 
      PR-957 (an anti-LMP7 agent) for RA treatment in vitro and in vivo and evaluate 
      its interaction with LMP7-mediated CD4(+) T cell imbalance. METHODS: Peripheral 
      blood mononuclear cells (PBMCs) were obtained from 30 RA patients and 30 healthy 
      controls. RA fibroblast-like synoviocytes (RA-FLSs) and CD4(+) T cells were 
      isolated from RA patients and then cocultured with PR-957 and/or LMP7 
      overexpression adenovirus (Ad-LMP7). Collagen-induced arthritis (CIA) mice were 
      constructed and then treated with PR-957 and/or Ad-LMP7. RESULTS: LMP7 was higher 
      in RA patients (versus healthy controls) and positively correlated with T helper 
      (Th)1 cells, the Th1/Th2 ratio, Th17 cells, and the Th17/Treg ratio but not with 
      Th2 or T regulatory (Treg) cells. PR-957 reduced Th1 and Th17 cells but increased 
      Th2 and Treg cells in RA-CD4(+) T cells, and this effect was partially reversed 
      by Ad-LMP7 transfection. Interestingly, when cocultured with RA-CD4(+) T cells, 
      PR-957 increased RA-FLS apoptosis and decreased its invasive ability, viability, 
      and inflammation, as suggested by IL-6, CCL2, MMP1, and MMP3; however, these 
      phenomena were weakened in RA-FLSs without RA-CD4(+) T cell coculture. In 
      addition, Ad-LMP7 transfection attenuated the above effects of PR-957. In CIA 
      mice, PR-957 decreased the arthritis score, synovial hyperproliferation and 
      articular injury, inflammation in the synovium and serum, and the imbalance of 
      Th1/Th2 and Th17/Treg in the spleen, and these effects were attenuated by 
      Ad-LMP7. CONCLUSION: PR-957 ameliorates RA progression and inflammation by 
      repressing LMP7-mediated CD4(+) T cell imbalance.
CI  - Copyright (c) 2023. Published by Elsevier B.V.
FAU - Liu, Qingyang
AU  - Liu Q
AD  - Department of Clinical Laboratory, Wuxi Ninth People's Hospital Affiliated to 
      Soochow University, Wuxi 214000, Jiangsu, China.
FAU - Shen, Jin
AU  - Shen J
AD  - Department of Clinical Laboratory, Wuxi Ninth People's Hospital Affiliated to 
      Soochow University, Wuxi 214000, Jiangsu, China.
FAU - Wang, Jian
AU  - Wang J
AD  - Department of Joint Surgery, Wuxi Ninth People's Hospital Affiliated to Soochow 
      University, Wuxi 214000, Jiangsu, China.
FAU - Xia, Jinjun
AU  - Xia J
AD  - Department of Clinical Laboratory, Wuxi Ninth People's Hospital Affiliated to 
      Soochow University, Wuxi 214000, Jiangsu, China.
FAU - Yin, Jian
AU  - Yin J
AD  - Department of Clinical Laboratory, Wuxi Ninth People's Hospital Affiliated to 
      Soochow University, Wuxi 214000, Jiangsu, China.
FAU - Cheng, Guowei
AU  - Cheng G
AD  - Department of Clinical Laboratory, Wuxi Ninth People's Hospital Affiliated to 
      Soochow University, Wuxi 214000, Jiangsu, China.
FAU - Qian, Ximing
AU  - Qian X
AD  - Department of Clinical Laboratory, Wuxi Ninth People's Hospital Affiliated to 
      Soochow University, Wuxi 214000, Jiangsu, China.
FAU - Jiang, Yun
AU  - Jiang Y
AD  - Department of Clinical Laboratory, Wuxi Ninth People's Hospital Affiliated to 
      Soochow University, Wuxi 214000, Jiangsu, China.
FAU - Ge, Xin
AU  - Ge X
AD  - Department of Critical Care Medicine, Wuxi Ninth People's Hospital Affiliated to 
      Soochow University, Wuxi 214000, Jiangsu, China. Electronic address: 
      gexin2021@suda.edu.cn.
FAU - Wang, Qiubo
AU  - Wang Q
AD  - Department of Clinical Laboratory, Wuxi Ninth People's Hospital Affiliated to 
      Soochow University, Wuxi 214000, Jiangsu, China. Electronic address: 
      wangqiubo2020@suda.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20230914
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
RN  - 0 (Peptides)
RN  - 0 (PR-957)
RN  - EC 3.4.25.1 (LMP7 protein)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - *Arthritis, Experimental/drug therapy
MH  - *Arthritis, Rheumatoid/drug therapy
MH  - Inflammation
MH  - Leukocytes, Mononuclear
MH  - Peptides/pharmacology
MH  - T-Lymphocytes, Regulatory
MH  - Th1 Cells
MH  - Th17 Cells
MH  - CD4-Positive T-Lymphocytes
OTO - NOTNLM
OT  - CD4(+) T cell imbalance
OT  - Low molecular mass polypeptide 7
OT  - PR-957
OT  - Progression and inflammation
OT  - Rheumatoid arthritis
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/09/17 00:41
MHDA- 2023/10/23 01:18
CRDT- 2023/09/16 18:05
PHST- 2023/06/27 00:00 [received]
PHST- 2023/08/10 00:00 [revised]
PHST- 2023/08/23 00:00 [accepted]
PHST- 2023/10/23 01:18 [medline]
PHST- 2023/09/17 00:41 [pubmed]
PHST- 2023/09/16 18:05 [entrez]
AID - S1567-5769(23)01185-2 [pii]
AID - 10.1016/j.intimp.2023.110860 [doi]
PST - ppublish
SO  - Int Immunopharmacol. 2023 Nov;124(Pt A):110860. doi: 
      10.1016/j.intimp.2023.110860. Epub 2023 Sep 14.