PMID- 30878820
OWN - NLM
STAT- MEDLINE
DCOM- 20191212
LR  - 20191217
IS  - 1878-1705 (Electronic)
IS  - 1567-5769 (Linking)
VI  - 71
DP  - 2019 Jun
TI  - TGR5 agonist INT-777 mitigates inflammatory response in human endometriotic 
      stromal cells: A therapeutic implication for endometriosis.
PG  - 93-99
LID - S1567-5769(18)31443-7 [pii]
LID - 10.1016/j.intimp.2019.02.044 [doi]
AB  - Endometriosis is a condition characterized by the presence of endometrial tissues 
      outside the uterus. Endometriotic stromal cells (ESCs) are known to undergo 
      regeneration and are linked to the causation of endometriosis. Activation of 
      stromal cells by local inflammatory cytokines is proposed to be one of the 
      mechanisms of endometriosis development. Takeda-G-protein-receptor-5 (TGR5) is a 
      G protein-coupled bile acid receptor that plays multiple roles in various cells 
      and tissues. In this study, we show that activation of TGR5 by its specific 
      agonist, INT-777, protects ESCs from inflammation and oxidative stress induced by 
      tumor necrosis factor-alpha (TNF-alpha). TGR5 is fairly expressed in cultured ESCs, and 
      TNF-alpha treatment suppresses TGR5 expression. Activation of TGR5 by its synthetic 
      agonist, INT-777, dramatically reduces the production of pro-inflammatory 
      cytokines and adhesion molecules by TNF-alpha, including interleukin-6 (IL-6), 
      interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), intercellular 
      adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). 
      Moreover, INT-777 suppresses TNF-alpha-induced NADPH oxidase 4 (NOX4) expression and 
      ameliorates cellular oxidative stress. Mechanistically, our findings demonstrate 
      that INT-777 suppresses TNF-alpha-induced c-Jun N-terminal kinase (JNK) activation 
      via suppression of p-JNK. INT-777 inhibits TNF-alpha-induced activation of the 
      activator protein-1 (AP-1) pathway owing to its suppression of c-Jun and c-fos as 
      well as transfected AP-1 promoter. INT-777 also inhibits nuclear factor-kappaB 
      (NF-kappaB) activation as revealed by its suppression of TNF-alpha-induced nuclear p65 
      accumulation and NF-kappaB promoter. Collectively, our data indicate that activation 
      of TGR5 by its agonist has protective effects against inflammation and reactive 
      oxygen species (ROS) in cytokine-induced activation of ESCs. Therefore, INT-777 
      may have an implication in the clinical treatment of endometriosis.
CI  - Copyright (c) 2019. Published by Elsevier B.V.
FAU - Lyu, Dan
AU  - Lyu D
AD  - Department of Pain Management, Tianjin First Center Hospital, Tianjin, China.
FAU - Tang, Ning
AU  - Tang N
AD  - Reproductive Medicine Center, The 960th Hospital of the PLA Joint Logistics 
      Support Force, Jinan, China.
FAU - Wang, Jianye
AU  - Wang J
AD  - Reproductive Medicine Center, The 960th Hospital of the PLA Joint Logistics 
      Support Force, Jinan, China.
FAU - Zhang, Yan
AU  - Zhang Y
AD  - Reproductive Medicine Center, The 960th Hospital of the PLA Joint Logistics 
      Support Force, Jinan, China.
FAU - Chang, Jianfang
AU  - Chang J
AD  - Reproductive Medicine Center, The 960th Hospital of the PLA Joint Logistics 
      Support Force, Jinan, China.
FAU - Liu, Zhitao
AU  - Liu Z
AD  - Reproductive Medicine Center, The 960th Hospital of the PLA Joint Logistics 
      Support Force, Jinan, China.
FAU - Liu, Haiping
AU  - Liu H
AD  - Reproductive Medicine Center, The 960th Hospital of the PLA Joint Logistics 
      Support Force, Jinan, China. Electronic address: jeniss512@163.com.
LA  - eng
PT  - Journal Article
DEP - 20190314
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
RN  - 0 (6alpha-ethyl-23(S)-methylcholic acid)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Cholic Acids)
RN  - 0 (GPBAR1 protein, human)
RN  - 0 (Inflammation Mediators)
RN  - 0 (NF-kappa B)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
SB  - IM
MH  - Cell Adhesion Molecules/metabolism
MH  - Cell Line
MH  - Cholic Acids/pharmacology/*therapeutic use
MH  - Endometriosis/*drug therapy
MH  - Endometrium/*pathology
MH  - Female
MH  - Humans
MH  - Inflammation
MH  - Inflammation Mediators/metabolism
MH  - MAP Kinase Kinase 4/metabolism
MH  - NADPH Oxidase 4/metabolism
MH  - NF-kappa B/metabolism
MH  - Oxidative Stress
MH  - Receptors, G-Protein-Coupled/*agonists
MH  - Signal Transduction
MH  - Stromal Cells/*physiology
MH  - Transcription Factor AP-1/genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
OTO - NOTNLM
OT  - AP-1
OT  - Endometriotic stromal cells (ESCs)
OT  - INT-777
OT  - JNK
OT  - NF-kappaB
OT  - TGR5
OT  - TNF-alpha
EDAT- 2019/03/18 06:00
MHDA- 2019/12/18 06:00
CRDT- 2019/03/18 06:00
PHST- 2018/12/25 00:00 [received]
PHST- 2019/02/16 00:00 [revised]
PHST- 2019/02/25 00:00 [accepted]
PHST- 2019/03/18 06:00 [pubmed]
PHST- 2019/12/18 06:00 [medline]
PHST- 2019/03/18 06:00 [entrez]
AID - S1567-5769(18)31443-7 [pii]
AID - 10.1016/j.intimp.2019.02.044 [doi]
PST - ppublish
SO  - Int Immunopharmacol. 2019 Jun;71:93-99. doi: 10.1016/j.intimp.2019.02.044. Epub 
      2019 Mar 14.