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Jia Q, Zhou HR, Shi Y, Pestka JJ.
Docosahexaenoic acid consumption inhibits Vomitoxin (deoxynivalenol)
(DON) -induced CREB/ATF1 activation and IL-6 gene transcription
in mouse macrophages.
J Nutr. 2006 Feb;136(2):366-72.
Center for Integrative Toxicology, Michigan State University,
East Lansing, MI, USA.
The mycotoxin deoxynivalenol (DON) induces IgA nephropathy in
mice by upregulating IL-6 expression, which is suppressed by
(n-3) PUFA consumption. The purpose of this study was to test
the hypothesis that consumption of the (n-3) PUFA
docosahexaenoic acid (DHA) interferes with DON-induced
transcriptional and post-transcriptional upregulation of IL-6
mRNA in murine macrophages. DON evoked expression of IL-6 mRNA
and IL-6 heterogenous nuclear RNA (hnRNA), an indicator of
ongoing IL-6 transcription, in macrophages elicited from mice
fed control AIN-93G diet for 4 wk, whereas expression of both
RNA species was suppressed in macrophages from mice fed AIN-93G
modified to contain 30 g DHA/kg diet for the same time period.
DON enhanced IL-6 mRNA stability similarly in macrophages from
control and DHA-fed mice suggesting that (n-3) PUFA effects were
not post-transcriptional. DON upregulated binding activity of
cAMP response element binding protein (CREB) and activator
protein (AP-1) to their respective consensus sequences in
nuclear extracts from control-fed mice, whereas both activities
were suppressed in nuclear extracts from DHA-fed mice. DON
induced phosphorylation of CREB at Ser-133 and ATF1 at Ser-63 as
well as intranuclear binding of phospho-CREB/ATF1 to the cis
element of the IL-6 promoter in control macrophages, whereas
both activities were inhibited in macrophages from DHA-fed mice.
DHA consumption blocked DON-induced phosphorylation of the CREB
kinase AKT. Inhibition of AKT suppressed both CREB/ATF1
phosphorylation and IL-6 transcription. These data suggest that
DHA consumption suppresses DON-induced IL-6 transcription in
macrophages in part by interfering with AKT-dependent
phosphorylation and subsequent binding of CREB/ATF1 to the IL-6
promoter.
PMID: 16424113
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