Three distinct groups of TNF-activated genes. (A) Average expression profiles of genes in groups I (red, peak at 0.5 h), II (green, 2h) and III (blue, 12h) in 3T3 fibroblasts stimulated with recombinant mouse TNF. Figure was reproduced from . (B) Simulation profiles of the 3 groups of genes using the initial TNFR1 model. (C) Simulation of the modified TNFR1 model with transcriptional delay and novel feedback mechanisms (solid lines) or with transcriptional delay and without feedback mechanisms (dotted lines). (D,E) Proposed novel feedback pathway to provide additional signaling flux through translation of group I genes into proteins for autocrine signaling (red lines) (D) or cytosolic positive feedback (blue lines) (E). Red and blue dotted lines indicate several intermediary molecular reactions (refer to Table 1). X
refer to the novel intermediates included in the updated TNFR1 model (refer to Table 1, reactions 48–65), and Y refers to a novel transcription factor, such as interferon regulatory factor (IRF).