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 language | English |
|---|---|
| Pages (from-to) | 1266-1274 |
| Number of pages | 9 |
| Journal | Journal of Immunology |
| Volume | 188 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 1 2012 |
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All Science Journal Classification (ASJC) codes
- Immunology
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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 journal › Article
}
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
C2 - 22219331
AN - SCOPUS:84863046014
VL - 188
SP - 1266
EP - 1274
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 3
ER -