title: Docosahexaenoic acid consumption inhibits deoxynivalenol-induced CREB/ATF1 activation and IL-6 gene transcription in mouse macrophages.
abstract: 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.
authors.affiliation: Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA.
authors.forename: Qunshan
authors.initials: Q
authors.lastname: Jia
authors.forename: Hui-Ren
authors.initials: HR
authors.lastname: Zhou
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Shi
authors.forename: James J
authors.initials: JJ
authors.lastname: Pestka
mesh_terms: D051697:Activating Transcription Factor 1 / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015850:Interleukin-6 / Q000235:genetics*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics; D014255:Trichothecenes / Q000494:pharmacology*
chemical_list: D051697:Activating Transcription Factor 1; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D015850:Interleukin-6; D010743:Phospholipids; D012333:RNA, Messenger; D014255:Trichothecenes; D004281:Docosahexaenoic Acids; D051057:Proto-Oncogene Proteins c-akt; C007262:deoxynivalenol