PMID- 34234507
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220424
IS  - 1178-7031 (Print)
IS  - 1178-7031 (Electronic)
IS  - 1178-7031 (Linking)
VI  - 14
DP  - 2021
TI  - Upregulation of COX-2 and PGE(2) Induced by TNF-alpha Mediated Through 
      TNFR1/MitoROS/PKCalpha/P38 MAPK, JNK1/2/FoxO1 Cascade in Human Cardiac Fibroblasts.
PG  - 2807-2824
LID - 10.2147/JIR.S313665 [doi]
AB  - PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) has been shown to exert as a pathogenic 
      factor in cardiac fibrosis and heart failure which were associated with the 
      up-regulation of cyclooxygenase (COX)-2/prostaglandin E(2) (PGE(2)) axis. 
      However, whether TNF-alpha-induced COX-2/PGE(2) upregulation mediated through 
      ROS-dependent cascade remains elusive in human cardiac fibroblasts (HCFs). This 
      study aims to address the underlying mechanisms of TNF-alpha-induced COX-2/PGE(2) 
      expression. METHODS: Here, we used TNF receptor neutralizing antibody (TNFR nAb), 
      pharmacologic inhibitors, and siRNAs to dissect the involvement of signaling 
      components examined by Western blot and ELISA in TNF-alpha-mediated responses in 
      HCFs. MitoSOX Red was used to measure mitoROS generation. Isolation of 
      subcellular fractions was performed to determine membrane translocation of PKCalpha. 
      Promoter luciferase assay and chromatin immunoprecipitation (ChIP) assay were 
      used to determine the role of transcription factor. RESULTS: We found that TNF-alpha 
      time- and concentration-dependently upregulated COX-2 protein and mRNA expression 
      as well as PGE(2) synthesis which was attenuated by TNFR1 nAb, the inhibitor of 
      mitochondrial ROS scavenger (MitoTEMPO), protein kinase C [(PKC)alpha, Go6976], p38 
      MAPK [p38 inhibitor VIII, (p38i VIII)], JNK1/2 (SP600125), or forkhead box 
      protein O1 [(FoxO1), AS1842856], and transfection with their respective siRNAs in 
      HCFs. TNF-alpha-stimulated PKCalpha phosphorylation was inhibited by TNFR1 nAb, 
      MitoTEMPO, or Go6976. TNF-alpha stimulated phosphorylation of p38 MAPK and JNK1/2 was 
      attenuated by TNFR1 nAb, MitoTEMPO, Go6976, and their inhibitors p38i VIII and 
      SP600125. Moreover, TNF-alpha-triggered FoxO1 phosphorylation was abolished by 
      AS1842856, TNFR1 nAb, and its upstream inhibitors MitoTEMPO, Go6976, p38i VIII, 
      and SP600125. Phosphorylation of FoxO1 could enhance its interaction with the 
      COX-2 promoter element revealed by ChIP assay, which was attenuated by AS1842856. 
      CONCLUSION: Our results suggested that TNF-alpha-induced COX-2/PGE(2) upregulation is 
      mediated through TNFR1-dependent MitoROS/PKCalpha/p38 MAPK and JNK1/2 cascade to 
      activate FoxO1 binding with the COX-2 promoter in HCFs.
CI  - (c) 2021 Yang et al.
FAU - Yang, Chuen-Mao
AU  - Yang CM
AUID- ORCID: 0000-0002-3208-5438
AD  - Department of Pharmacology, College of Medicine, China Medical University, 
      Taichung, 40402, Taiwan.
AD  - Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, 
      Taichung, 40402, Taiwan.
AD  - Department of Post-Baccalaureate Veterinary Medicine, College of Medical and 
      Health Science, Asia University, Wufeng, Taichung, 41354, Taiwan.
FAU - Yang, Chien-Chung
AU  - Yang CC
AUID- ORCID: 0000-0003-2325-5017
AD  - Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at 
      Tao-Yuan, Kwei-San, Tao-Yuan, 33302, Taiwan.
AD  - School of Traditional Chinese Medicine, College of Medicine, Chang Gung 
      University, Kwei-San, Tao-Yuan, 33302, Taiwan.
FAU - Hsiao, Li-Der
AU  - Hsiao LD
AD  - Department of Pharmacology, College of Medicine, China Medical University, 
      Taichung, 40402, Taiwan.
FAU - Yu, Chia-Ying
AU  - Yu CY
AD  - Department of Pharmacology, College of Medicine, China Medical University, 
      Taichung, 40402, Taiwan.
FAU - Tseng, Hui-Ching
AU  - Tseng HC
AD  - Department of Pharmacology, College of Medicine, China Medical University, 
      Taichung, 40402, Taiwan.
FAU - Hsu, Chih-Kai
AU  - Hsu CK
AD  - Department of Pharmacology, College of Medicine, China Medical University, 
      Taichung, 40402, Taiwan.
FAU - Situmorang, Jiro Hasegawa
AU  - Situmorang JH
AUID- ORCID: 0000-0003-3288-6814
AD  - Department of Pharmacology, College of Medicine, China Medical University, 
      Taichung, 40402, Taiwan.
LA  - eng
PT  - Journal Article
DEP - 20210628
PL  - New Zealand
TA  - J Inflamm Res
JT  - Journal of inflammation research
JID - 101512684
PMC - PMC8254141
OTO - NOTNLM
OT  - COX-2
OT  - FoxO1
OT  - PGE2
OT  - PKC-alpha
OT  - TNF-alpha
OT  - mitochondrial ROS
COIS- The authors report no conflicts of interest in this work.
EDAT- 2021/07/09 06:00
MHDA- 2021/07/09 06:01
PMCR- 2021/06/28
CRDT- 2021/07/08 06:37
PHST- 2021/04/06 00:00 [received]
PHST- 2021/05/28 00:00 [accepted]
PHST- 2021/07/08 06:37 [entrez]
PHST- 2021/07/09 06:00 [pubmed]
PHST- 2021/07/09 06:01 [medline]
PHST- 2021/06/28 00:00 [pmc-release]
AID - 313665 [pii]
AID - 10.2147/JIR.S313665 [doi]
PST - epublish
SO  - J Inflamm Res. 2021 Jun 28;14:2807-2824. doi: 10.2147/JIR.S313665. eCollection 
      2021.