Characterization of an NF-kappaB-regulated, miRNA-146a-mediated down-regulation of complement factor H (CFH) in metal-sulfate-stressed human brain cells.
Micro RNAs (miRNAs) represent a family of small ribonucleic acids (RNAs) that are post-transcriptional regulators of messenger RNA (mRNA) complexity. Brain cells maintain distinct populations of miRNAs that support physiologically normal patterns of expression, however, certain miRNA abundances are significantly altered in neurodegenerative disorders such as Alzheimer's disease (AD). Here we provide evidence in human neural (HN) cells of an aluminum-sulfate- and reactive oxygen species (ROS)-mediated up-regulation of an NF-kappaB-sensitive miRNA-146a that down-regulates the expression of complement factor H (CFH), an important repressor of inflammation. This NF-kappaB-miRNA-146a-CFH signaling circuit is known to be similarly affected by Abeta42 peptides and in AD brain. These aluminum-sulfate-inducible events were not observed in parallel experiments using iron-, magnesium-, or zinc-sulfate-stressed HN cells. An NF-kappaB-containing miRNA-146a-promoter-luciferase reporter construct transfected into HN cells showed significant up-regulation of miRNA-146a after aluminum-sulfate treatment that corresponded to decreased CFH gene expression. These data suggest that (1) as in AD brain, NF-kappaB-sensitive, miRNA-146a-mediated, modulation of CFH gene expression may contribute to inflammatory responses in aluminum-stressed HN cells, and (2) underscores the potential of nanomolar aluminum to drive genotoxic mechanisms characteristic of neurodegenerative disease processes.
Pogue
Aileen I
AI
Neuroscience Center and Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Li
Yuan Yuan
YY
Cui
Jian-Guo
JG
Zhao
Yuhai
Y
Kruck
Theodore P A
TP
Percy
Maire E
ME
Tarr
Matthew A
MA
Lukiw
Walter J
WJ
D000534:Alum Compounds / Q000633:toxicity*; D000544:Alzheimer Disease / Q000139:chemically induced / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D001483:Base Sequence; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D017242:Complement Factor H / Q000235:genetics*; D015536:Down-Regulation; D006801:Humans; D008278:Magnesium Sulfate / Q000494:pharmacology; D035683:MicroRNAs / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000819:agonists / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
D000534:Alum Compounds; D016229:Amyloid beta-Peptides; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); C041524:aluminum sulfate; D008278:Magnesium Sulfate; D017242:Complement Factor H