Function of C/EBPdelta 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-kappaB, C/EBPdelta and ATF3 that controls inflammatory responses. We mathematically modeled transcriptional regulation of the genes encoding interleukin 6 and C/EBPdelta and experimentally confirmed the prediction that the combination of an initiator (NF-kappaB), an amplifier (C/EBPdelta) 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.
Litvak
Vladimir
V
Institute for Systems Biology, Seattle, Washington, USA.
Ramsey
Stephen A
SA
Rust
Alistair G
AG
Zak
Daniel E
DE
Kennedy
Kathleen A
KA
Lampano
Aaron E
AE
Nykter
Matti
M
Shmulevich
Ilya
I
Aderem
Alan
A
D051700:Activating Transcription Factor 3 / Q000276:immunology* / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D002478:Cells, Cultured; D004927:Escherichia coli Infections / Q000276:immunology; D053263:Gene Regulatory Networks; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D016328:NF-kappa B / Q000276:immunology / Q000502:physiology; D049490:Systems Biology; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000502:physiology
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C497253:Cebpd protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051743:CCAAT-Enhancer-Binding Protein-delta