PMID- 26222138
OWN - NLM
STAT- MEDLINE
DCOM- 20160513
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 7
DP  - 2015
TI  - NRF2 Signaling Negatively Regulates Phorbol-12-Myristate-13-Acetate (PMA)-Induced 
      Differentiation of Human Monocytic U937 Cells into Pro-Inflammatory Macrophages.
PG  - e0134235
LID - 10.1371/journal.pone.0134235 [doi]
LID - e0134235
AB  - Blood monocytes are recruited to injured tissue sites and differentiate into 
      macrophages, which protect against pathogens and repair damaged tissues. Reactive 
      oxygen species (ROS) are known to be an important contributor to monocytes' 
      differentiation and macrophages' function. NF-E2-related factor 2 (NRF2), a 
      transcription factor regulating cellular redox homeostasis, is known to be a 
      critical modulator of inflammatory responses. We herein investigated the role of 
      NRF2 in macrophage differentiation using the human monocytic U937 cell line and 
      phorbol-12-myristate-13-acetate (PMA). In U937 cells with NRF2 silencing, 
      PMA-stimulated cell adherence was significantly facilitated when compared to 
      control U937 cells. Both transcript and protein levels for pro-inflammatory 
      cytokines, including interleukine-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha 
      (TNFalpha) were highly elevated in PMA-stimulated NRF2-silenced U937 compared to the 
      control. In addition, PMA-inducible secretion of monocyte chemotactic protein 1 
      (MCP-1) was significantly high in NRF2-silenced U937. As an underlying mechanism, 
      we showed that NRF2-knockdown U937 retained high levels of cellular ROS and 
      endoplasmic reticulum (ER) stress markers expression; and subsequently, 
      PMA-stimulated levels of Ca2+ and PKCalpha were greater in NRF2-knockdown U937 cells, 
      which caused enhanced nuclear accumulation of nuclear factor-ҡB (NFҡB) p50 and 
      extracellular signal-regulated kinase (ERK)-1/2 phosphorylation. Whereas the 
      treatment of NRF2-silenced U937 cells with pharmacological inhibitors of NFҡB or 
      ERK1/2 largely blocked PMA-induced IL-1beta and IL-6 expression, indicating that 
      these pathways are associated with cell differentiation. Taken together, our 
      results suggest that the NRF2 system functions to suppress PMA-stimulated U937 
      cell differentiation into pro-inflammatory macrophages and provide evidence that 
      the ROS-PKCalpha-ERK-NFҡB axis is involved in PMA-facilitated differentiation of 
      NRF2-silenced U937 cells.
FAU - Song, Min-Gu
AU  - Song MG
AD  - College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongsangbuk-do 712-749, 
      Republic of Korea.
FAU - Ryoo, In-Geun
AU  - Ryoo IG
AD  - College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 
      420-743, Republic of Korea.
FAU - Choi, Hye-Young
AU  - Choi HY
AD  - College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 
      420-743, Republic of Korea.
FAU - Choi, Bo-Hyun
AU  - Choi BH
AD  - College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 
      420-743, Republic of Korea.
FAU - Kim, Sang-Tae
AU  - Kim ST
AD  - Seoul National University Bundang Hospital, Sungnam, Gyeonggi-do 463-707, 
      Republic of Korea.
FAU - Heo, Tae-Hwe
AU  - Heo TH
AD  - College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 
      420-743, Republic of Korea.
FAU - Lee, Joo Young
AU  - Lee JY
AD  - College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 
      420-743, Republic of Korea.
FAU - Park, Pil-Hoon
AU  - Park PH
AD  - College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongsangbuk-do 712-749, 
      Republic of Korea.
FAU - Kwak, Mi-Kyoung
AU  - Kwak MK
AD  - College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 
      420-743, Republic of Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150729
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cytokines)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NF-kappa B p50 Subunit)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (NFKB1 protein, human)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.11.13 (PRKCA protein, human)
RN  - EC 2.7.11.13 (Protein Kinase C-alpha)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Calcium/metabolism
MH  - Cell Differentiation/drug effects/immunology
MH  - Cytokines/metabolism
MH  - Endoplasmic Reticulum Stress
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - MAP Kinase Signaling System/drug effects
MH  - Macrophages/*drug effects/immunology/*metabolism
MH  - Monocytes/*drug effects/immunology/*metabolism
MH  - NF-E2-Related Factor 2/antagonists & inhibitors/genetics/*metabolism
MH  - NF-kappa B p50 Subunit/metabolism
MH  - Protein Kinase C-alpha/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/drug effects
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - U937 Cells
PMC - PMC4519053
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/07/30 06:00
MHDA- 2016/05/14 06:00
PMCR- 2015/07/29
CRDT- 2015/07/30 06:00
PHST- 2015/03/12 00:00 [received]
PHST- 2015/07/07 00:00 [accepted]
PHST- 2015/07/30 06:00 [entrez]
PHST- 2015/07/30 06:00 [pubmed]
PHST- 2016/05/14 06:00 [medline]
PHST- 2015/07/29 00:00 [pmc-release]
AID - PONE-D-15-10869 [pii]
AID - 10.1371/journal.pone.0134235 [doi]
PST - epublish
SO  - PLoS One. 2015 Jul 29;10(7):e0134235. doi: 10.1371/journal.pone.0134235. 
      eCollection 2015.