PMID- 33919055
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221217
IS  - 2076-3921 (Print)
IS  - 2076-3921 (Electronic)
IS  - 2076-3921 (Linking)
VI  - 10
IP  - 5
DP  - 2021 Apr 21
TI  - Auranofin-Mediated NRF2 Induction Attenuates Interleukin 1 Beta Expression in 
      Alveolar Macrophages.
LID - 10.3390/antiox10050632 [doi]
LID - 632
AB  - BACKGROUND: Alveolar macrophages (AMs) are resident inflammatory cells in the 
      lung that serve as early sentinels of infection or injury. We have identified 
      thioredoxin reductase 1 inhibition by gold compounds increases activation of 
      nuclear factor erythroid 2-related factor 2 (NRF2)-dependent pathways to 
      attenuate inflammatory responses. The present studies utilized murine alveolar 
      macrophages (MH-S) to test the hypothesis that the gold compound, auranofin 
      (AFN), decreases interleukin (IL)-1beta expression through NRF2-mediated 
      interactions with nuclear factor kappa-light-chain-enhancer of activated B cells 
      (NF-kappaB) pathway genes and/or increases in glutathione synthesis. METHODS: MH-S 
      cells were treated with AFN and lipopolysaccharide (LPS) and analyzed at 6 and 24 
      h. The Il1b promoter was analyzed by chromatin immunoprecipitation for direct 
      interaction with NRF2. RESULTS: Expression of IL-1beta, p-IkappaBalpha, p-p65 NF-kB, and 
      NOD-, LRR-, and pyrin domain-containing protein 3 were elevated by LPS exposure, 
      but only IL-1beta expression was suppressed by AFN treatment. Both AFN and LPS 
      treatments increased cellular glutathione levels, but attenuation of glutathione 
      synthesis by buthionine sulfoximine (BSO) did not alter expression of Il-1beta. 
      Analysis revealed direct NRF2 binding to the Il1b promoter which was enhanced by 
      AFN and inhibited the transcriptional activity of DNA polymerase II. CONCLUSIONS: 
      Our data demonstrate that AFN-induced NRF2 activation directly suppresses IL-1beta 
      synthesis independent of NFkappaB and glutathione-mediated antioxidant mechanisms. 
      NRF2 binding to the promoter region of IL1beta directly inhibits transcription of 
      the IL1beta gene. Collectively, our research suggests that gold compounds elicit 
      NRF2-dependent pulmonary protection by suppressing macrophage-mediated 
      inflammation.
FAU - Wall, Stephanie B
AU  - Wall SB
AD  - Neonatal Redox Biology Laboratory, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
AD  - Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL 
      35294, USA.
FAU - Li, Rui
AU  - Li R
AD  - Neonatal Redox Biology Laboratory, University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
AD  - Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL 
      35294, USA.
FAU - Butler, Brittany
AU  - Butler B
AD  - Section of Neonatology, University of Colorado School of Medicine and Children's 
      Hospital Colorado, Aurora, CO 80045, USA.
FAU - Burg, Ashley R
AU  - Burg AR
AD  - Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 
      35294, USA.
FAU - Tse, Hubert M
AU  - Tse HM
AUID- ORCID: 0000-0001-5861-7597
AD  - Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 
      35294, USA.
FAU - Larson-Casey, Jennifer L
AU  - Larson-Casey JL
AUID- ORCID: 0000-0001-7238-7986
AD  - Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at 
      Birmingham, Birmingham, AL 35294, USA.
FAU - Carter, A Brent
AU  - Carter AB
AD  - Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at 
      Birmingham, Birmingham, AL 35294, USA.
AD  - Birmingham Veterans Affairs Medical Center, Birmingham, AL 35233, USA.
FAU - Wright, Clyde J
AU  - Wright CJ
AD  - Section of Neonatology, University of Colorado School of Medicine and Children's 
      Hospital Colorado, Aurora, CO 80045, USA.
AD  - Department of Pediatrics, University of Colorado School of Medicine and 
      Children's Hospital Colorado, Aurora, CO 80045, USA.
FAU - Rogers, Lynette K
AU  - Rogers LK
AUID- ORCID: 0000-0003-3413-5379
AD  - Center for Perinatal Research, Abigail Wexner Research Institute at Nationwide 
      Children's Hospital, Columbus, OH 43215, USA.
FAU - Tipple, Trent E
AU  - Tipple TE
AD  - Section of Neonatal-Perinatal Medicine, University of Oklahoma Health Sciences 
      Center, Oklahoma City, OK 73104, USA.
LA  - eng
GR  - R01HL119280/HL/NHLBI NIH HHS/United States
GR  - R01 HL119280/HL/NHLBI NIH HHS/United States
GR  - R01HL132941/HL/NHLBI NIH HHS/United States
GR  - R01 ES015981/ES/NIEHS NIH HHS/United States
GR  - R01 HL132941/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20210421
PL  - Switzerland
TA  - Antioxidants (Basel)
JT  - Antioxidants (Basel, Switzerland)
JID - 101668981
PMC - PMC8143169
OTO - NOTNLM
OT  - Il-1beta
OT  - NFkappaB
OT  - NRF2
OT  - auranofin
OT  - hyperoxia
COIS- The authors declare no conflict of interest.
EDAT- 2021/05/01 06:00
MHDA- 2021/05/01 06:01
PMCR- 2021/04/21
CRDT- 2021/04/30 01:11
PHST- 2021/02/22 00:00 [received]
PHST- 2021/04/01 00:00 [revised]
PHST- 2021/04/12 00:00 [accepted]
PHST- 2021/04/30 01:11 [entrez]
PHST- 2021/05/01 06:00 [pubmed]
PHST- 2021/05/01 06:01 [medline]
PHST- 2021/04/21 00:00 [pmc-release]
AID - antiox10050632 [pii]
AID - antioxidants-10-00632 [pii]
AID - 10.3390/antiox10050632 [doi]
PST - epublish
SO  - Antioxidants (Basel). 2021 Apr 21;10(5):632. doi: 10.3390/antiox10050632.