An NF-κB-sensitive micro RNA-146a-mediated inflammatory circuit in alzheimer disease and in stressed human brain cells

Walter J. Lukiw, Yuhai Zhao, Guo Cui Jian

Research output: Contribution to journalArticle

303 Citations (Scopus)

Abstract

Human brains retain discrete populations of micro RNA (miRNA) species that support homeostatic brain gene expression functions; however, specific miRNA abundance is significantly altered in neurological disorders such as Alzheimer disease (AD) when compared with age-matched controls. Here we provide evidence in AD brains of a specific up-regulation of an NF-κB-sensitive miRNA-146a highly complementary to the 3′-untranslated region of complement factor H (CFH), an important repressor of the inflammatory response of the brain. Up-regulation of miRNA-146a coupled to down-regulation of CFH was observed in AD brain and in interleukin-1β, Aβ42, and/or oxidatively stressed human neural (HN) cells in primary culture. Transfection of HN cells using an NF-κB-containing pre-miRNA-146a promoter-luciferase reporter construct in stressed HN cells showed significant up-regulation of luciferase activity that paralleled decreases in CFH gene expression. Treatment of stressed HN cells with the NF-κB inhibitor pyrollidine dithiocarbamate or the resveratrol analog CAY10512 abrogated this response. Incubation of an antisense oligonucleotide to miRNA-146a (anti-miRNA-146a; AM-146a) was found to restore CFH expression levels. These data indicate that NF-κB-sensitive miRNA-146a-mediated modulation of CFH gene expressionmayin part regulate an inflammatory response inAD brain and in stressed HN cell models of AD and illustrate the potential for anti-miRNAs as an effective therapeutic strategy against pathogenic inflammatory signaling.

Original languageEnglish
Pages (from-to)31315-31322
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number46
DOIs
StatePublished - Nov 14 2008

Fingerprint

MicroRNAs
Brain
Alzheimer Disease
Complement Factor H
Networks (circuits)
Up-Regulation
Luciferases
Gene expression
Gene Expression
Primary Cell Culture
Antisense Oligonucleotides
3' Untranslated Regions
Nervous System Diseases
Interleukin-1
Transfection
Down-Regulation
Genes
Modulation
Population

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

An NF-κB-sensitive micro RNA-146a-mediated inflammatory circuit in alzheimer disease and in stressed human brain cells. / Lukiw, Walter J.; Zhao, Yuhai; Jian, Guo Cui.

In: Journal of Biological Chemistry, Vol. 283, No. 46, 14.11.2008, p. 31315-31322.

Research output: Contribution to journalArticle

@article{3d744339ada2490b9351fdc1e54dbd73,
title = "An NF-κB-sensitive micro RNA-146a-mediated inflammatory circuit in alzheimer disease and in stressed human brain cells",
abstract = "Human brains retain discrete populations of micro RNA (miRNA) species that support homeostatic brain gene expression functions; however, specific miRNA abundance is significantly altered in neurological disorders such as Alzheimer disease (AD) when compared with age-matched controls. Here we provide evidence in AD brains of a specific up-regulation of an NF-κB-sensitive miRNA-146a highly complementary to the 3′-untranslated region of complement factor H (CFH), an important repressor of the inflammatory response of the brain. Up-regulation of miRNA-146a coupled to down-regulation of CFH was observed in AD brain and in interleukin-1β, Aβ42, and/or oxidatively stressed human neural (HN) cells in primary culture. Transfection of HN cells using an NF-κB-containing pre-miRNA-146a promoter-luciferase reporter construct in stressed HN cells showed significant up-regulation of luciferase activity that paralleled decreases in CFH gene expression. Treatment of stressed HN cells with the NF-κB inhibitor pyrollidine dithiocarbamate or the resveratrol analog CAY10512 abrogated this response. Incubation of an antisense oligonucleotide to miRNA-146a (anti-miRNA-146a; AM-146a) was found to restore CFH expression levels. These data indicate that NF-κB-sensitive miRNA-146a-mediated modulation of CFH gene expressionmayin part regulate an inflammatory response inAD brain and in stressed HN cell models of AD and illustrate the potential for anti-miRNAs as an effective therapeutic strategy against pathogenic inflammatory signaling.",
author = "Lukiw, {Walter J.} and Yuhai Zhao and Jian, {Guo Cui}",
year = "2008",
month = "11",
day = "14",
doi = "10.1074/jbc.M805371200",
language = "English",
volume = "283",
pages = "31315--31322",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "46",

}

TY - JOUR

T1 - An NF-κB-sensitive micro RNA-146a-mediated inflammatory circuit in alzheimer disease and in stressed human brain cells

AU - Lukiw, Walter J.

AU - Zhao, Yuhai

AU - Jian, Guo Cui

PY - 2008/11/14

Y1 - 2008/11/14

N2 - Human brains retain discrete populations of micro RNA (miRNA) species that support homeostatic brain gene expression functions; however, specific miRNA abundance is significantly altered in neurological disorders such as Alzheimer disease (AD) when compared with age-matched controls. Here we provide evidence in AD brains of a specific up-regulation of an NF-κB-sensitive miRNA-146a highly complementary to the 3′-untranslated region of complement factor H (CFH), an important repressor of the inflammatory response of the brain. Up-regulation of miRNA-146a coupled to down-regulation of CFH was observed in AD brain and in interleukin-1β, Aβ42, and/or oxidatively stressed human neural (HN) cells in primary culture. Transfection of HN cells using an NF-κB-containing pre-miRNA-146a promoter-luciferase reporter construct in stressed HN cells showed significant up-regulation of luciferase activity that paralleled decreases in CFH gene expression. Treatment of stressed HN cells with the NF-κB inhibitor pyrollidine dithiocarbamate or the resveratrol analog CAY10512 abrogated this response. Incubation of an antisense oligonucleotide to miRNA-146a (anti-miRNA-146a; AM-146a) was found to restore CFH expression levels. These data indicate that NF-κB-sensitive miRNA-146a-mediated modulation of CFH gene expressionmayin part regulate an inflammatory response inAD brain and in stressed HN cell models of AD and illustrate the potential for anti-miRNAs as an effective therapeutic strategy against pathogenic inflammatory signaling.

AB - Human brains retain discrete populations of micro RNA (miRNA) species that support homeostatic brain gene expression functions; however, specific miRNA abundance is significantly altered in neurological disorders such as Alzheimer disease (AD) when compared with age-matched controls. Here we provide evidence in AD brains of a specific up-regulation of an NF-κB-sensitive miRNA-146a highly complementary to the 3′-untranslated region of complement factor H (CFH), an important repressor of the inflammatory response of the brain. Up-regulation of miRNA-146a coupled to down-regulation of CFH was observed in AD brain and in interleukin-1β, Aβ42, and/or oxidatively stressed human neural (HN) cells in primary culture. Transfection of HN cells using an NF-κB-containing pre-miRNA-146a promoter-luciferase reporter construct in stressed HN cells showed significant up-regulation of luciferase activity that paralleled decreases in CFH gene expression. Treatment of stressed HN cells with the NF-κB inhibitor pyrollidine dithiocarbamate or the resveratrol analog CAY10512 abrogated this response. Incubation of an antisense oligonucleotide to miRNA-146a (anti-miRNA-146a; AM-146a) was found to restore CFH expression levels. These data indicate that NF-κB-sensitive miRNA-146a-mediated modulation of CFH gene expressionmayin part regulate an inflammatory response inAD brain and in stressed HN cell models of AD and illustrate the potential for anti-miRNAs as an effective therapeutic strategy against pathogenic inflammatory signaling.

UR - http://www.scopus.com/inward/record.url?scp=57649119790&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=57649119790&partnerID=8YFLogxK

U2 - 10.1074/jbc.M805371200

DO - 10.1074/jbc.M805371200

M3 - Article

C2 - 18801740

AN - SCOPUS:57649119790

VL - 283

SP - 31315

EP - 31322

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 46

ER -