科研之友
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摘要
Aberrant cellular responses to proinflammatory cytokines, such as TNF-alpha, 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-alpha 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-alpha-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-alpha-induced suppression of PCAF expression. Promoter recruitment of PCAF was shown to be associated with TNF-alpha-induced transcription of inflammatory genes. Intriguingly, pretreatment of cells with TNF-alpha inhibited transcription of inflammatory genes in response to subsequent TNF-alpha stimulation. Overexpression of PCAF or inhibition of miR-181a/b function with anti-miRs attenuated the inhibitory effects of TNF-alpha pretreatment on epithelial inflammatory response to subsequent TNF-alpha stimulation. Downregulation of PCAF and the inhibitory effects of TNF-alpha pretreatment on liver epithelial inflammatory response were further confirmed in a mouse model of TNF-alpha i.p. injection. These data suggest that PCAF is a target for miR-181a/b, and downregulation of PCAF by TNF-alpha 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. The Journal of Immunology, 2012, 188: 1266-1274.
- 出版日期2012-2-1
- 单位四川大学
