Understanding NF-kappaB signaling via mathematical modeling

Abstract

Mammalian inflammatory signaling, for which NF-kappaB is a principal transcription factor, is an exquisite example of how cellular signaling pathways can be regulated to produce different yet specific responses to different inflammatory insults. Mathematical models, tightly linked to experiment, have been instrumental in unraveling the forms of regulation in NF-kappaB signaling and their underlying molecular mechanisms. Our initial model of the IkappaB-NF-kappaB signaling module highlighted the role of negative feedback in the control of NF-kappaB temporal dynamics and gene expression. Subsequent studies sparked by this work have helped to characterize additional feedback loops, the input-output behavior of the module, crosstalk between multiple NF-kappaB-activating pathways, and NF-kappaB oscillations. We anticipate that computational techniques will enable further progress in the NF-kappaB field, and the signal transduction field in general, and we discuss potential upcoming developments.

Figure 1

Schematic of NF-κB dynamics in response to persistent TNFα. (A) Oscillatory time course of NF-κB in response to TNFα in cells whose only classical IκB is IκBα (see also BioModels database http://www.ebi.ac.uk/biomodels, accession ID BIOMD0000000139). (B) Characteristic biphasic time course of NF-κB signaling in response to TNFα in various wild-type cells. NF-κB activity peaks around 30 min, drops to basal levels around 1 h, and rises to an intermediate level thereafter (see also BioModels accession ID BIOMD0000000140).

Figure 2

Feedback loops in NF-κB signaling. IKK may be activated by the TNFα signaling pathway as well as the MyD88-dependent arm of the LPS signaling pathway. IKK leads to NF-κB activity, which is regulated by a negative feedback loop involving IκB (described in detail in Box 1), as depicted in the lower center. TNFα-induced NF-κB activity also leads to A20 expression, and subsequent decrease in IKK activation. Also, the Trif-dependent arm of the LPS-signaling pathway activates the transcription factor interferon regulatory factor-3 (IRF3), leading to TNFα expression and subsequent autocrine signaling. Thus, A20 and TNF form feedback loops that regulate NF-κB activity.

Figure 3

Schematic of stimulus-specific NF-κB responses. Both TNFα and LPS activate NF-κB through IKK, yet the NF-κB responses to each are different. In response to a 45-min pulse of TNFα, NF-κB activity rises quickly then terminates after approximately 60 min (bottom right). In contrast, in response to a 45-min pulse of LPS, NF-κB activity rises slowly over 2 h (bottom left). The NF-κB response correlates with the IKK activity profile, which is highly peaked in response to TNFα (upper right) but sustained in response to LPS (upper left). This illustrates how IKK helps to mediate stimulus-specific NF-κB responses.