Inflammation is the external manifestation of the body's protective response to tissue damage or injury. Substances migrate to the site of damage to repair the surrounding tissue. On the flip side, chronic inflammation actually causes damage to tissues. It plays a role in a plethora of common diseases ranging from asthma to osteoarthritis. Transcription factors that control gene expression play a role in the inflammatory response. Some members of the nuclear factor-kappaB (NF-kB) family regulate multiple steps. EU support of the project 'Role of nonlinear dynamics of NF-kB in inflammation' (NONLIN-KB) gave scientists the opportunity to study oscillations of NF-kB between the cytoplasm and the nucleus and to analyse them mathematically. Experimentally, inducing and observing the oscillations required construction of a special setup for imaging of cells with fluorescently tagged NF-kB. The setup enables microfluidic perfusion of the cells with various biochemical factors and simultaneous imaging. Quantifying the responses of hundreds of cells necessitated development of specialised software. The algorithms use quantifiers from non-linear dynamics theory to describe observed dynamics through a time-series analysis. The team faithfully reproduced experimental observations with a simplified model exploiting only three layers of regulation. It should be an important tool for predicting possible mechanisms of NF-kB regulation of transcription. With these powerful tools in their hands, researchers discovered that the oscillations are much more complicated than previously thought. They can be periodic or not, and can also begin spontaneously in the absence of stimuli. Under many conditions, the cells can exhibit coordinated dynamics or synchronous NF-kB oscillations. However, in the presence of periodic stimuli, the coordinated behaviour can be quite heterogeneous across cells. The drug dexamethasone commonly used to treat inflammatory diseases was observed for its effect on stimulation-induced oscillations. It not only modified the dynamics of oscillations but also the transcription profile, providing a potential switch to control inflammatory responses. The multidisciplinary NONLIN-KB project applied non-linear dynamics to the study of intracellular fluctuations in space and time of a transcription factor controlling the inflammatory response. The models have provided insight into stimulus-induced changes and point to potential targets for therapy.
Non-linear dynamics, inflammation, nuclear factor-kappaB, NF-kB, oscillations