PMID- 33859345
OWN - NLM
STAT- MEDLINE
DCOM- 20220316
LR  - 20230202
IS  - 1745-7254 (Electronic)
IS  - 1671-4083 (Print)
IS  - 1671-4083 (Linking)
VI  - 43
IP  - 2
DP  - 2022 Feb
TI  - TNF-alpha impairs EP4 signaling through the association of TRAF2-GRK2 in primary 
      fibroblast-like synoviocytes.
PG  - 401-416
LID - 10.1038/s41401-021-00654-z [doi]
AB  - Our previous study showed that chronic treatment with tumor necrosis factor-alpha 
      (TNF-alpha) decreased cAMP concentration in fibroblast-like synoviocytes (FLSs) of 
      collagen-induced arthritis (CIA) rats. In this study we investigated how TNF-alpha 
      impairs cAMP homeostasis, particularly clarifying the potential downstream 
      molecules of TNF-alpha and prostaglandin receptor 4 (EP4) signaling that would 
      interact with each other. Using a cAMP FRET biosensor PM-ICUE3, we demonstrated 
      that TNF-alpha (20 ng/mL) blocked ONO-4819-triggered EP4 signaling, but not 
      Butaprost-triggered EP2 signaling in normal rat FLSs. We showed that TNF-alpha 
      (0.02-20 ng/mL) dose-dependently reduced EP4 membrane distribution in normal rat 
      FLS. TNF-alpha significantly increased TNF receptor 2 (TNFR2) expression and 
      stimulated proliferation in human FLS (hFLS) via ecruiting TNF 
      receptor-associated factor 2 (TRAF2) to cell membrane. More interestingly, we 
      revealed that TRAF2 interacted with G protein-coupled receptor kinase (GRK2) in 
      the cytoplasm of primary hFLS and helped to bring GRK2 to cell membrane in 
      response of TNF-alpha stimulation, the complex of TRAF2 and GRK2 then separated on 
      the membrane, and translocated GRK2 induced the desensitization and 
      internalization of EP4, leading to reduced production of intracellular cAMP. 
      Silencing of TRAF2 by siRNA substantially diminished TRAF2-GRK2 interaction, 
      blocked the translocation of GRK2, and resulted in upregulated expression of 
      membrane EP4 and intracellular cAMP. In CIA rats, administration of paroxetine to 
      inhibit GRK2 effectively improved the symptoms and clinic parameters with 
      significantly reduced joint synovium inflammation and bone destruction. These 
      results elucidate a novel form of cross-talk between TNFR (a cytokine receptor) 
      and EP4 (a typical G protein-coupled receptor) signaling pathways. The 
      interaction between TRAF2 and GRK2 may become a potential new drug target for the 
      treatment of inflammatory diseases.
CI  - (c) 2021. The Author(s), under exclusive licence to CPS and SIMM.
FAU - Tai, Yu
AU  - Tai Y
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of 
      Education, Hefei, 230032, China.
FAU - Huang, Bei
AU  - Huang B
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of 
      Education, Hefei, 230032, China.
AD  - Department of Pharmacy, Maanshan Hospital of Traditional Chinese Medicine, 
      Maanshan, 243000, China.
FAU - Guo, Pai-Pai
AU  - Guo PP
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of 
      Education, Hefei, 230032, China.
FAU - Wang, Zhen
AU  - Wang Z
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of 
      Education, Hefei, 230032, China.
FAU - Zhou, Zheng-Wei
AU  - Zhou ZW
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of 
      Education, Hefei, 230032, China.
FAU - Wang, Man-Man
AU  - Wang MM
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of 
      Education, Hefei, 230032, China.
FAU - Sun, Han-Fei
AU  - Sun HF
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of 
      Education, Hefei, 230032, China.
FAU - Hu, Yong
AU  - Hu Y
AD  - Department of Orthopedics, The First Affiliated Hospital of Anhui Medical 
      University, Hefei, 230032, China.
FAU - Xu, Sheng-Lin
AU  - Xu SL
AD  - Department of Orthopedics, The First Affiliated Hospital of Anhui Medical 
      University, Hefei, 230032, China.
FAU - Zhang, Ling-Ling
AU  - Zhang LL
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of 
      Education, Hefei, 230032, China.
FAU - Wang, Qing-Tong
AU  - Wang QT
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of 
      Education, Hefei, 230032, China. hfwqt727@163.com.
FAU - Wei, Wei
AU  - Wei W
AD  - Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of 
      Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of 
      Education, Hefei, 230032, China. wwei@ahmu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20210415
PL  - United States
TA  - Acta Pharmacol Sin
JT  - Acta pharmacologica Sinica
JID - 100956087
RN  - 0 (Receptors, Prostaglandin E, EP4 Subtype)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.15 (Grk2 protein, rat)
RN  - EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2)
SB  - IM
MH  - Animals
MH  - Arthritis, Experimental/metabolism
MH  - Fibroblasts/drug effects/metabolism
MH  - G-Protein-Coupled Receptor Kinase 2/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Prostaglandin E, EP4 Subtype/*antagonists & inhibitors
MH  - Signal Transduction/*drug effects
MH  - Synoviocytes/*drug effects/metabolism
MH  - TNF Receptor-Associated Factor 2/*metabolism
MH  - Tumor Necrosis Factor-alpha/*pharmacology
PMC - PMC8791952
OTO - NOTNLM
OT  - EP4
OT  - GRK2
OT  - TNFR2
OT  - TRAF2
OT  - fibroblast-like synoviocytes
OT  - rheumatoid arthritis
COIS- The authors declare no competing interests.
EDAT- 2021/04/17 06:00
MHDA- 2022/03/17 06:00
PMCR- 2023/02/01
CRDT- 2021/04/16 06:25
PHST- 2020/10/18 00:00 [received]
PHST- 2021/03/13 00:00 [accepted]
PHST- 2021/04/17 06:00 [pubmed]
PHST- 2022/03/17 06:00 [medline]
PHST- 2021/04/16 06:25 [entrez]
PHST- 2023/02/01 00:00 [pmc-release]
AID - 10.1038/s41401-021-00654-z [pii]
AID - 654 [pii]
AID - 10.1038/s41401-021-00654-z [doi]
PST - ppublish
SO  - Acta Pharmacol Sin. 2022 Feb;43(2):401-416. doi: 10.1038/s41401-021-00654-z. Epub 
      2021 Apr 15.