Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals

The innate immune system is like a double-edged sword: it is absolutely required for host defense against infection, but when uncontrolled, it can trigger a plethora of inflammatory diseases. Here we use systems- biology approaches to predict and confirm the existence of a gene- regulatory network involving dynamic interaction among the transcription factors NF-kappa B, C/EBP Omega and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of the genes encoding interleukin 6 and C/EBP delta and experimentally confirmed the prediction that the combination of an initiator (NF-kappa B), an amplifier (C/EBP delta) and an attenuator (ATF3) forms a regulatory circuit that discriminates between transient and persistent Toll-like receptor 4-induced signals. Our results suggest a mechanism that enables the innate immune system to detect the duration of infection and to respond appropriately.