NFAT and NFkappaB activation in T lymphocytes: a model of differential activation of gene expression.

Mathematical models for the regulation of the Ca(2+)-dependent transcription factors NFAT and NFkappaB that are involved in the activation of the immune and inflammatory responses in T lymphocytes have been developed. These pathways are important targets for drugs, which act as powerful immunosuppressants by suppressing activation of NFAT and NFkappaB in T cells. The models simulate activation and deactivation over physiological concentrations of Ca(2+), diacyl glycerol (DAG), and PKCtheta using single and periodic step increases. The model suggests the following: (1) the activation NFAT does not occur at low frequencies as NFAT requires calcineurin activated by Ca(2+) to remain dephosphorylated and in the nucleus; (2) NFkappaB is activated at lower Ca(2+) oscillation frequencies than NFAT as IkappaB is degraded in response to elevations in Ca(2+) allowing free NFkappaB to translocate into the nucleus; and (3) the degradation of IkappaB is essential for efficient translocation of NFkappaB to the nucleus. Through sensitivity analysis, the model also suggests that the largest controlling factor for NFAT activation is the dissociation/reassociation rate of the NFAT:calcineurin complex and the translocation rate of the complex into the nucleus and for NFkappaB is the degradation/resynthesis rate of IkappaB and the import rate of IkappaB into the nucleus.