NRF2 Signaling Negatively Regulates Phorbol-12-Myristate-13-Acetate (PMA)-Induced Differentiation of Human Monocytic U937 Cells into Pro-Inflammatory Macrophages

Title
NRF2 Signaling Negatively Regulates Phorbol-12-Myristate-13-Acetate (PMA)-Induced Differentiation of Human Monocytic U937 Cells into Pro-Inflammatory Macrophages
Author(s)
송민구류인근[류인근]최혜영[최혜영]최보현[최보현]김상태[김상태]허태회[허태회]이주영[이주영]박필훈곽미경[곽미경]
Keywords
PROTEIN-KINASE-C; I-KAPPA-B; ENDOPLASMIC-RETICULUM STRESS; OXIDATIVE STRESS; TRANSCRIPTION FACTOR; ANTIOXIDANT RESPONSE; CELLULAR STRESS; PHORBOL ESTERS; ACTIVATION; EXPRESSION
Issue Date
201507
Publisher
PUBLIC LIBRARY SCIENCE
Citation
PLOS ONE, v.10, no.7
Abstract
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-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) 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 PKC alpha were greater in NRF2-knockdown U937 cells, which caused enhanced nuclear accumulation of nuclear factor-kappa B (NF kappa B) p50 and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation. Whereas the treatment of NRF2-silenced U937 cells with pharmacological inhibitors of NF kappa B or ERK1/2 largely blocked PMA-induced IL-1 beta 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-PKC alpha-ERK-NF kappa B axis is involved in PMA-facilitated differentiation of NRF2-silenced U937 cells.
URI
http://hdl.handle.net/YU.REPOSITORY/31602http://dx.doi.org/10.1371/journal.pone.0134235
ISSN
1932-6203
Appears in Collections:
중앙도서관 > rims journal
약학대학 > 약학부 > Articles
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE