A modeled dynamic regulatory network of NF-κB and IL-6 mediated by miRNA

摘要

The inflammatory response is a rapid and complex physiological reaction to infection, which must be carefully modulated to remove pathogens and prevent the consequences of unregulated expression including cancer. MiRNAs are small noncoding RNAs that regulate protein-coding genes via post-transcriptional repression. Emerging evidence suggests that the role of miRNAs in the regulation of immune responses as well as inflammatory networks in various cell and tissue types. Here, we have constructed a mathematical model that integrates miR-21 and miR-146 expression into a signaling pathway to generate an in silico model for the process of inflammation. The results show that the negative feedback provided by miR-21 stimulates the propensity of oscillations in NF-κB and IL-6 activity, while the negative feedback provided by miR-146 dampens the oscillations of NF-κB and IL-6. This process is somewhat sensitive to the inputs of miR-21 and miR-146, suggesting that variations in the relative strength of the two feedbacks may provide for altered response dynamics to the same stimulus. Our findings reveal a novel regulatory module of two miRNA-mediated negative feedback loops that allows for the fine-tuning of the dynamics of key mediators in inflammation.