Modeling the NF-κB mediated inflammatory response predicts cytokine waves in tissue.

BACKGROUND: Waves propagating in "excitable media" is a reliable way to transmit signals in space. A fascinating example where living cells comprise such a medium is Dictyostelium D. which propagates waves of chemoattractant to attract distant cells. While neutrophils chemotax in a similar fashion as Dictyostelium D., it is unclear if chemoattractant waves exist in mammalian tissues and what mechanisms could propagate them. RESULTS: We propose that chemoattractant cytokine waves may naturally develop as a result of NF-κB response. Using a heuristic mathematical model of NF-κB-like circuits coupled in space we show that the known characteristics of NF-κB response favor cytokine waves. CONCLUSIONS: While the propagating wave of cytokines is generally beneficial for inflammation resolution, our model predicts that there exist special conditions that can cause chronic inflammation and re-occurrence of acute inflammatory response.

Modeling oscillatory control in NF-κB, p53 and Wnt signaling.

Oscillations are commonly observed in cellular behavior and span a wide range of timescales, from seconds in calcium signaling to 24 hours in circadian rhythms. In between lie oscillations with time periods of 1-5 hours seen in NF-κB, p53 and Wnt signaling, which play key roles in the immune system, cell growth/death and embryo development, respectively. In the first part of this article, we provide a brief overview of simple deterministic models of oscillations. In particular, we explain the mechanism of saturated degradation that has been used to model oscillations in the NF-κB, p53 and Wnt systems. The second part deals with the potential physiological role of oscillations. We use the simple models described earlier to explore whether oscillatory signals can encode more information than steady-state signals. We then discuss a few simple genetic circuits that could decode information stored in the average, amplitude or frequency of oscillations. The presence of frequency-detector circuit downstream of NF-κB or p53 would be a strong clue that oscillations are important for the physiological response of these signaling systems.

Kinetic enhancement of NF-kappaBxDNA dissociation by IkappaBalpha.

A hallmark of the NF-kappaB transcription response to inflammatory cytokines is the remarkably rapid rate of robust activation and subsequent signal repression. Although the rapidity of postinduction repression is explained partly by the fact that the gene for IkappaBalpha is strongly induced by NF-kappaB, the newly synthesized IkappaBalpha still must enter the nucleus and compete for binding to NF-kappaB with the very large number of kappaB sites in the DNA. We present results from real-time binding kinetic experiments, demonstrating that IkappaBalpha increases the dissociation rate of NF-kappaB from the DNA in a highly efficient kinetic process. Analysis of various IkappaB mutant proteins shows that this process requires the C-terminal PEST sequence and the weakly folded fifth and sixth ankyrin repeats of IkappaBalpha. Mutational stabilization of these repeats reduces the efficiency with which IkappaBalpha enhances the dissociation rate.