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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Respir+Cell+Mol+Biol
2016 ; 55
(1
): 58-71
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Cu,Zn-Superoxide Dismutase-Mediated Redox Regulation of Jumonji Domain Containing
3 Modulates Macrophage Polarization and Pulmonary Fibrosis
#MMPMID26699812
He C
; Larson-Casey JL
; Gu L
; Ryan AJ
; Murthy S
; Carter AB
Am J Respir Cell Mol Biol
2016[Jul]; 55
(1
): 58-71
PMID26699812
show ga
M2 macrophages are implicated in the development of pulmonary fibrosis as they
generate profibrotic signals. The polarization process, at least in part, is
regulated by epigenetic modulation. Because Cu,Zn-superoxide dismutase-induced
H2O2 can polarize macrophages to a profibrotic M2 phenotype, we hypothesized that
modulation of the redox state of the cell is involved in the epigenetic
modulation of the macrophage phenotype. In this study, we show that signal
transducer and activator of transcription 6 (STAT6) regulates Jumonji domain
containing (Jmjd) 3, a histone H3 lysine 27 demethylase, and mutation of a
redox-sensitive cysteine in STAT6 attenuates jmjd3 expression. Moreover, Jmjd3
deficiency abrogates profibrotic M2 gene expression. Treatment with leflunomide,
which reduces mitochondrial reactive oxygen species production and tyrosine
phosphorylation, inhibits jmjd3 expression and M2 polarization, as well as
development of a fibrotic phenotype. Taken together, these observations provide
evidence that the redox regulation of Jmjd3 is a unique regulatory mechanism for
Cu,Zn-superoxide dismutase-mediated profibrotic M2 polarization. Furthermore,
leflunomide, which reduces reactive oxygen species production and tyrosine
phosphorylation, may prove to be therapeutic in the treatment of asbestos-induced
pulmonary fibrosis.