Iron chelator induces THP-1 cell differentiation potentially by modulating intracellular glutathione levels.
Iron chelators have been implicated to modulate certain inflammatory mediators and regulate inflammatory processes. Here we report that iron chelator deferoxamine (DFO) induces differentiation of monocytic THP-1 cells into functional macrophages. DFO rapidly phosphorylated both extracellular signal-regulated kinase (ERK) and p38 kinase. Blockade of ERK signaling by the MEK1/2 inhibitor PD098059 abolished DFO-induced class A scavenger receptor (SR-A) expression and phagocytic activity, indicating that ERK cascades mediate the induction of THP-1 differentiation. In contrast, in cells treated with the p38 inhibitor SB203580 or transfected with the dominant-negative variant of p38 kinase, DFO-mediated ERK activation became more prominent, and the induction of SR-A expression and phagocytic activity were significantly increased. Interestingly, differentiation by DFO was associated with decrease in cellular glutathione (GSH) level. Both MAPK inhibitors did not influence the GSH level; however, treatment with ferric citrate (Fe3+) or N-acetyl-cysteine, a major precursor of GSH, markedly recovered GSH level to a normal extent, along with the significant decrease of differentiation. Collectively, these results indicate that oxidative stress by DFO and the resulting activation of ERK cascade play dominant roles in the process of THP-1 differentiation, while p38 acts as a negative signal transmitter.
Seo
Geom-Seog
GS
Digestive Disease Research Institute, Wonkwang University School of Medicine, Iksan, Chonbuk 570-749, Korea.
Lee
Sung-Hee
SH
Choi
Suck-Chei
SC
Choi
Eun-Young
EY
Oh
Hyun-Mee
HM
Choi
Eun-Ju
EJ
Park
Do-Sim
DS
Kim
Sang-Wook
SW
Kim
Tae-Hyeon
TH
Nah
Yong-Ho
YH
Kim
Soonhag
S
Kim
Sang-Hyun
SH
You
Sun-Hae
SH
Jun
Chang-Duk
CD
D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D005978:Glutathione / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051117:Scavenger Receptors, Class A / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D007502:Iron Chelating Agents; D051117:Scavenger Receptors, Class A; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D003676:Deferoxamine