Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=29693039
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Demethylase JMJD6 as a New Regulator of Interferon Signaling: Effects of HCV and
Ethanol Metabolism
#MMPMID29693039
Ganesan M
; Tikhanovich I
; Vangimalla SS
; Dagur RS
; Wang W
; Poluektova LI
; Sun Y
; Mercer DF
; Tuma D
; Weinman SA
; Kharbanda KK
; Osna NA
Cell Mol Gastroenterol Hepatol
2018[]; 5
(2
): 101-112
PMID29693039
show ga
BACKGROUND & AIMS: Alcohol-induced progression of hepatitis C virus (HCV)
infection is related to dysfunction of innate immunity in hepatocytes.
Endogenously produced interferon (IFN)? induces activation of
interferon-stimulated genes (ISGs) via triggering of the Janus kinase-signal
transducer and activator of transcription 1 (STAT1) pathway. This activation
requires protein methyltransferase 1-regulated arginine methylation of STAT1.
Here, we aimed to study whether STAT1 methylation also depended on the levels of
demethylase jumonji domain-containing 6 protein (JMJD6) and whether ethanol and
HCV affect JMJD6 expression in hepatocytes. METHODS: Huh7.5-CYP (RLW) cells and
hepatocytes were exposed to acetaldehyde-generating system (AGS) and 50 mmol/L
ethanol, respectively. JMJD6 messenger RNA and protein expression were measured
by real-time polymerase chain reaction and Western blot. IFN?-activated cells
either overexpressing JMJD6 or with knocked-down JMJD6 expression were tested for
STAT1 methylation, ISG activation, and HCV RNA. In vivo studies have been
performed on C57Bl/6 mice (expressing HCV structural proteins or not) or chimeric
mice with humanized livers fed control or ethanol diets. RESULTS: AGS exposure to
cells up-regulated JMJD6 expression in RLW cells. These results were corroborated
by ethanol treatment of primary hepatocytes. The promethylating agent betaine
reversed the effects of AGS/ethanol. Similar results were obtained in vivo, when
mice were fed control/ethanol with and without betaine supplementation.
Overexpression of JMJD6 suppressed STAT1 methylation, IFN?-induced ISG
activation, and increased HCV-RNA levels. In contrast, JMJD6 silencing enhanced
STAT1 methylation, ISG stimulation by IFN?, and attenuated HCV-RNA expression in
Huh7.5 cells. CONCLUSIONS: We conclude that arginine methylation of STAT1 is
suppressed by JMJD6. Both HCV and acetaldehyde increase JMJD6 levels, thereby
impairing STAT1 methylation and innate immunity protection in hepatocytes exposed
to the virus and/or alcohol.
free
free
free
