title: A model for how signal duration can determine distinct outcomes of gene transcription programs.
abstract: The reason why IL-6 induces a pro-inflammatory response, while IL-10 induces an anti-inflammatory response, despite both cytokines activating the same transcription factor, STAT3, is not well understood. It is known that IL-6 induces a transient STAT3 signal and that IL-10 induces a sustained STAT3 signal due to the STAT3-induced inhibitor SOCS3's ability to bind to the IL-6R and not the IL-10R. We sought to develop a general transcriptional network that is capable of translating sustained signals into one response, while translating transient signals into a second response. The general structure of such a network is that the transcription factor STAT3 can induce both an inflammatory response and an anti-inflammatory response by inducing two different genes. The anti-inflammatory gene can bind to and inhibit the inflammatory gene's production and the inflammatory gene can bind to its own promoter and induce its own transcription in the absence of the signal. One prediction that can be made from such a network is that in SOCS3-/- mice, where IL-6 induces a sustained STAT3 signal, that IL-6 would act as an anti-inflammatory cytokine, which has indeed been observed experimentally in the literature.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Fowler
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Arup K
authors.initials: AK
authors.lastname: Chakraborty
mesh_terms: D000818:Animals; D003198:Computer Simulation; D025461:Feedback, Physiological / Q000502:physiology; D053263:Gene Regulatory Networks / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10