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

ABSTRACT: Aberrant cellular responses to proinflammatory cytokines, such as TNF-?, 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-? 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-?-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-?-induced suppression of PCAF expression. Promoter recruitment of PCAF was shown to be associated with TNF-?-induced transcription of inflammatory genes. Intriguingly, pretreatment of cells with TNF-? inhibited transcription of inflammatory genes in response to subsequent TNF-? stimulation. Overexpression of PCAF or inhibition of miR-181a/b function with anti-miRs attenuated the inhibitory effects of TNF-? pretreatment on epithelial inflammatory response to subsequent TNF-? stimulation. Downregulation of PCAF and the inhibitory effects of TNF-? pretreatment on liver epithelial inflammatory response were further confirmed in a mouse model of TNF-? i.p. injection. These data suggest that PCAF is a target for miR-181a/b, and downregulation of PCAF by TNF-? 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.

SUBMITTER: Zhao J

PROVIDER: S-EPMC3262895 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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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 J Gong Ai-Yu AY Zhou Rui R Liu Jun J Eischeid Alex N AN Chen Xian-Ming XM

Journal of immunology (Baltimore, Md. : 1950) 20120104 3

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 prom ...[more]

PMID: 22219331

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Project description:MicroRNAs (miRNAs) are small non-coding RNAs (sRNA), that alter gene expression by binding to target messenger RNAs (mRNAs) and repressing translation. Dysregulated miRNA expression has been implicated in the pathogenesis of autoimmune diseases such as Sjögren's syndrome (SS). The aim of this study was to characterize the global profile of sRNAs in labial salivary glands (LSG) from SS-patients and to validate potential miRNA candidates implicated in glandular inflammation. LSG from 21 SS-patients and 9 sicca controls were analyzed. A global next generation sequencing (NGS)-based sRNA profiling approach was employed to identify direct targets whereby differentially expressed miRNAs were predicted using bioinformatics tools. miRNA levels were validated by TaqMan and target mRNA levels were determined by quantitative real-time PCR. We also performed in vitro assays using recombinant TNF-α. NGS shows that ~30% of sRNAs were miRNAs. In comparison with samples from sicca controls, four miRNAs were found differentially expressed in LSG from SS-patients with low focus score (LFS) and 18 from SS-patients with high focus score (HFS). The miRNA with the most significant changes identified by NGS was hsa-miR-181d-5p and downregulation was confirmed by TaqMan analysis. Levels of TNF-α mRNA, a direct target of hsa-miR-181d-5p, were significantly increased and negatively correlated with hsa-miR-181d-5p presence. Moreover, positive correlations between TNF-α transcript levels, focus score, ESSDAI, and autoantibody levels were also detected. Furthermore, TNF-α stimulation decreased hsa-miR-181d-5p levels in vitro. Downregulation of hsa-miR-181d-5p in LSG from SS-patients could contribute to the glandular pro-inflammatory environment by deregulation of its direct target TNF-α. Further dissection of the pathophysiological mechanisms underlying the hsa-miR-181d-5p-mediated action in inflammatory conditions could be useful to evaluate the benefits of increasing hsa-miR-181d-5p levels for restoration of salivary gland epithelial cell architecture and function.

Dataset Information

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

Publications

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

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