Downregulation of PCAF by miR-181a/b provides feedback regulation to TNF-α-induced transcription of proinflammatory genes in liver epithelial cells

Jian Zhao, Ai Yu Gong, Rui Zhou, Jun Liu, Alex N. Eischeid, Xian-Ming Chen

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Aberrant cellular responses to proinflammatory cytokines, such as TNF-α, are pathogenic features in most chronic inflammatory diseases. A variety of extracellular and intracellular feedback pathways has evolved to prevent an inappropriate cellular reaction to these proinflammatory cytokines. In this study, we report that TNF-α treatment of human and mouse cholangiocytes and hepatocytes downregulated expression of p300/CBP-associated factor (PCAF), a coactivator and an acetyltransferase that promotes histone acetylation and gene transcription. Of these upregulated microRNAs in TNF-α-treated cells, miR-181a/b (miR-181a and miR-181b) suppressed translation of PCAF mRNA. Functional manipulation of miR-181a/b caused reciprocal alterations in PCAF protein expression in cultured cholangiocytes and hepatocytes. Inhibition of miR-181a/b function with anti-miRs blocked TNF-α-induced suppression of PCAF expression. Promoter recruitment of PCAF was shown to be associated with TNF-α-induced transcription of inflammatory genes. Intriguingly, pretreatment of cells with TNF-α inhibited transcription of inflammatory genes in response to subsequent TNF-α stimulation. Overexpression of PCAF or inhibition of miR-181a/b function with anti-miRs attenuated the inhibitory effects of TNF-α pretreatment on epithelial inflammatory response to subsequent TNF-α stimulation. Downregulation of PCAF and the inhibitory effects of TNF-α pretreatment on liver epithelial inflammatory response were further confirmed in a mouse model of TNF-α i.p. injection. These data suggest that PCAF is a target for miR-181a/b, and downregulation of PCAF by TNF-α provides negative feedback regulation to inflammatory reactions in liver epithelial cells, a process that may be relevant to the epigenetic fine-tuning of epithelial inflammatory processes in general.

Original languageEnglish
Pages (from-to)1266-1274
Number of pages9
JournalJournal of Immunology
Volume188
Issue number3
DOIs
StatePublished - Feb 1 2012

Fingerprint

Down-Regulation
Epithelial Cells
Liver
Genes
Hepatocytes
Cytokines
Histone Acetyltransferases
p300-CBP-associated factor
Acetylation
MicroRNAs
Epigenomics
Chronic Disease
Messenger RNA
Injections
Proteins

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Downregulation of PCAF by miR-181a/b provides feedback regulation to TNF-α-induced transcription of proinflammatory genes in liver epithelial cells. / Zhao, Jian; Gong, Ai Yu; Zhou, Rui; Liu, Jun; Eischeid, Alex N.; Chen, Xian-Ming.

In: Journal of Immunology, Vol. 188, No. 3, 01.02.2012, p. 1266-1274.

Research output: Contribution to journalArticle

@article{d9bc5045d75f4b898eaa06d118d3be04,
title = "Downregulation of PCAF by miR-181a/b provides feedback regulation to TNF-α-induced transcription of proinflammatory genes in liver epithelial cells",
abstract = "Aberrant cellular responses to proinflammatory cytokines, such as TNF-α, are pathogenic features in most chronic inflammatory diseases. A variety of extracellular and intracellular feedback pathways has evolved to prevent an inappropriate cellular reaction to these proinflammatory cytokines. In this study, we report that TNF-α treatment of human and mouse cholangiocytes and hepatocytes downregulated expression of p300/CBP-associated factor (PCAF), a coactivator and an acetyltransferase that promotes histone acetylation and gene transcription. Of these upregulated microRNAs in TNF-α-treated cells, miR-181a/b (miR-181a and miR-181b) suppressed translation of PCAF mRNA. Functional manipulation of miR-181a/b caused reciprocal alterations in PCAF protein expression in cultured cholangiocytes and hepatocytes. Inhibition of miR-181a/b function with anti-miRs blocked TNF-α-induced suppression of PCAF expression. Promoter recruitment of PCAF was shown to be associated with TNF-α-induced transcription of inflammatory genes. Intriguingly, pretreatment of cells with TNF-α inhibited transcription of inflammatory genes in response to subsequent TNF-α stimulation. Overexpression of PCAF or inhibition of miR-181a/b function with anti-miRs attenuated the inhibitory effects of TNF-α pretreatment on epithelial inflammatory response to subsequent TNF-α stimulation. Downregulation of PCAF and the inhibitory effects of TNF-α pretreatment on liver epithelial inflammatory response were further confirmed in a mouse model of TNF-α i.p. injection. These data suggest that PCAF is a target for miR-181a/b, and downregulation of PCAF by TNF-α provides negative feedback regulation to inflammatory reactions in liver epithelial cells, a process that may be relevant to the epigenetic fine-tuning of epithelial inflammatory processes in general.",
author = "Jian Zhao and Gong, {Ai Yu} and Rui Zhou and Jun Liu and Eischeid, {Alex N.} and Xian-Ming Chen",
year = "2012",
month = "2",
day = "1",
doi = "10.4049/jimmunol.1101976",
language = "English",
volume = "188",
pages = "1266--1274",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "3",

}

TY - JOUR

T1 - Downregulation of PCAF by miR-181a/b provides feedback regulation to TNF-α-induced transcription of proinflammatory genes in liver epithelial cells

AU - Zhao, Jian

AU - Gong, Ai Yu

AU - Zhou, Rui

AU - Liu, Jun

AU - Eischeid, Alex N.

AU - Chen, Xian-Ming

PY - 2012/2/1

Y1 - 2012/2/1

N2 - Aberrant cellular responses to proinflammatory cytokines, such as TNF-α, are pathogenic features in most chronic inflammatory diseases. A variety of extracellular and intracellular feedback pathways has evolved to prevent an inappropriate cellular reaction to these proinflammatory cytokines. In this study, we report that TNF-α treatment of human and mouse cholangiocytes and hepatocytes downregulated expression of p300/CBP-associated factor (PCAF), a coactivator and an acetyltransferase that promotes histone acetylation and gene transcription. Of these upregulated microRNAs in TNF-α-treated cells, miR-181a/b (miR-181a and miR-181b) suppressed translation of PCAF mRNA. Functional manipulation of miR-181a/b caused reciprocal alterations in PCAF protein expression in cultured cholangiocytes and hepatocytes. Inhibition of miR-181a/b function with anti-miRs blocked TNF-α-induced suppression of PCAF expression. Promoter recruitment of PCAF was shown to be associated with TNF-α-induced transcription of inflammatory genes. Intriguingly, pretreatment of cells with TNF-α inhibited transcription of inflammatory genes in response to subsequent TNF-α stimulation. Overexpression of PCAF or inhibition of miR-181a/b function with anti-miRs attenuated the inhibitory effects of TNF-α pretreatment on epithelial inflammatory response to subsequent TNF-α stimulation. Downregulation of PCAF and the inhibitory effects of TNF-α pretreatment on liver epithelial inflammatory response were further confirmed in a mouse model of TNF-α i.p. injection. These data suggest that PCAF is a target for miR-181a/b, and downregulation of PCAF by TNF-α provides negative feedback regulation to inflammatory reactions in liver epithelial cells, a process that may be relevant to the epigenetic fine-tuning of epithelial inflammatory processes in general.

AB - Aberrant cellular responses to proinflammatory cytokines, such as TNF-α, are pathogenic features in most chronic inflammatory diseases. A variety of extracellular and intracellular feedback pathways has evolved to prevent an inappropriate cellular reaction to these proinflammatory cytokines. In this study, we report that TNF-α treatment of human and mouse cholangiocytes and hepatocytes downregulated expression of p300/CBP-associated factor (PCAF), a coactivator and an acetyltransferase that promotes histone acetylation and gene transcription. Of these upregulated microRNAs in TNF-α-treated cells, miR-181a/b (miR-181a and miR-181b) suppressed translation of PCAF mRNA. Functional manipulation of miR-181a/b caused reciprocal alterations in PCAF protein expression in cultured cholangiocytes and hepatocytes. Inhibition of miR-181a/b function with anti-miRs blocked TNF-α-induced suppression of PCAF expression. Promoter recruitment of PCAF was shown to be associated with TNF-α-induced transcription of inflammatory genes. Intriguingly, pretreatment of cells with TNF-α inhibited transcription of inflammatory genes in response to subsequent TNF-α stimulation. Overexpression of PCAF or inhibition of miR-181a/b function with anti-miRs attenuated the inhibitory effects of TNF-α pretreatment on epithelial inflammatory response to subsequent TNF-α stimulation. Downregulation of PCAF and the inhibitory effects of TNF-α pretreatment on liver epithelial inflammatory response were further confirmed in a mouse model of TNF-α i.p. injection. These data suggest that PCAF is a target for miR-181a/b, and downregulation of PCAF by TNF-α provides negative feedback regulation to inflammatory reactions in liver epithelial cells, a process that may be relevant to the epigenetic fine-tuning of epithelial inflammatory processes in general.

UR - http://www.scopus.com/inward/record.url?scp=84863046014&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863046014&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1101976

DO - 10.4049/jimmunol.1101976

M3 - Article

VL - 188

SP - 1266

EP - 1274

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 3

ER -