Downregulation of PCAF by miR-181a/b provides feedback regulation to TNF-α-induced transcription of proinflammatory genes in liver epithelial cells.
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.
Key Laboratory of Biological Resource and Ecological Environment, Ministry of Education, College of Life Science, Sichuan University, Chengdu 610064, China.
Jian
J
Zhao
Ai-Yu
AY
Gong
Rui
R
Zhou
Jun
J
Liu
Alex N
AN
Eischeid
Xian-Ming
XM
Chen
D000818:Animals; D015536:Down-Regulation / Q000187:drug effects*; D025461:Feedback, Physiological; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors*; D000099224:p300-CBP-Associated Factor
D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C540193:MIrn181 microRNA, human; C529100:mirn181 microRNA, mouse